63 results on '"Hirsch, HH."'
Search Results
2. Determinants of SARS-CoV-2 transmission to guide vaccination strategy in an urban area.
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Brüningk, SC, Klatt, J, Stange, M, Mari, A, Brunner, M, Roloff, T-C, Seth-Smith, HMB, Schweitzer, M, Leuzinger, K, Søgaard, KK, Albertos Torres, D, Gensch, A, Schlotterbeck, A-K, Nickel, CH, Ritz, N, Heininger, U, Bielicki, J, Rentsch, K, Fuchs, S, Bingisser, R, Siegemund, M, Pargger, H, Ciardo, D, Dubuis, O, Buser, A, Tschudin-Sutter, S, Battegay, M, Schneider-Sliwa, R, Borgwardt, KM, Hirsch, HH, Egli, A, Brüningk, SC, Klatt, J, Stange, M, Mari, A, Brunner, M, Roloff, T-C, Seth-Smith, HMB, Schweitzer, M, Leuzinger, K, Søgaard, KK, Albertos Torres, D, Gensch, A, Schlotterbeck, A-K, Nickel, CH, Ritz, N, Heininger, U, Bielicki, J, Rentsch, K, Fuchs, S, Bingisser, R, Siegemund, M, Pargger, H, Ciardo, D, Dubuis, O, Buser, A, Tschudin-Sutter, S, Battegay, M, Schneider-Sliwa, R, Borgwardt, KM, Hirsch, HH, and Egli, A
- Abstract
Transmission chains within small urban areas (accommodating ∼30 per cent of the European population) greatly contribute to case burden and economic impact during the ongoing coronavirus pandemic and should be a focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in a European urban area, Basel-City (Switzerland). We combined detailed epidemiological, intra-city mobility and socio-economic data sets with whole-genome sequencing during the first SARS-CoV-2 wave. For this, we succeeded in sequencing 44 per cent of all reported cases from Basel-City and performed phylogenetic clustering and compartmental modelling based on the dominating viral variant (B.1-C15324T; 60 per cent of cases) to identify drivers and patterns of transmission. Based on these results we simulated vaccination scenarios and corresponding healthcare system burden (intensive care unit (ICU) occupancy). Transmissions were driven by socio-economically weaker and highly mobile population groups with mostly cryptic transmissions which lacked genetic and identifiable epidemiological links. Amongst more senior population transmission was clustered. Simulated vaccination scenarios assuming 60-90 per cent transmission reduction and 70-90 per cent reduction of severe cases showed that prioritising mobile, socio-economically weaker populations for vaccination would effectively reduce case numbers. However, long-term ICU occupation would also be effectively reduced if senior population groups were prioritised, provided there were no changes in testing and prevention strategies. Reducing SARS-CoV-2 transmission through vaccination strongly depends on the efficacy of the deployed vaccine. A combined strategy of protecting risk groups by extensive testing coupled with vaccination of the drivers of transmission (i.e. highly mobile groups) would be most effective at
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- 2022
3. Posoleucel for BK Polyomavirus in Kidney Transplant Recipients.
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Wilhelm M, Geng A, Schaub S, and Hirsch HH
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- 2024
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4. BK Polyomavirus (BKPyV) Serotype-Specific Antibody Responses in Blood Donors and Kidney Transplant Recipients with and without new-onset BKPyV-DNAemia: A Swiss Transplant Cohort Study.
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Hillenbrand CA, Bani DA, Follonier O, Kaur A, Weissbach FH, Wernli M, Wilhelm M, Leuzinger K, Binet I, Bochud PY, Golshayan D, Hirzel C, Manuel O, Mueller NJ, Schaub S, Schachtner T, Van Delden C, and Hirsch HH
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BK polyomavirus (BKPyV) causes premature renal failure in 10%-30% of kidney transplant recipients (KTRs). Current guidelines recommend screening for new-onset BKPyV-DNAemia/nephropathy and reducing immunosuppression to regain BKPyV-specific immune control. Since BKPyV encompasses 4 major genotype(gt)-encoded serotypes (st1,-2,-3,-4), st-specific antibodies may inform risk and course of BKPyV-DNAemia/nephropathy. Using BKPyV st-virus-like particle (VLP) ELISA, we analyzed plasma from 399 blood donors (BDs) and 428 KTRs (134 KTR-cases with BKPyV-DNAemia, 294 KTR-controls). BDs were anti-BKPyV-VLP IgG-seropositive in 85% compared to 93% of KTRs at T0 (p<0.001). Anti-st1 were predominant in both groups followed by anti-st4, anti-st2, and anti-st3. Antibody levels and quadruple sero-reactivity at T0 were higher in KTR-controls than in KTR-cases (p=0.026) or in BDs (p<0.001). In KTR-cases, anti-st increased post-transplant (p<0.0001) and independently of ongoing or cleared BKPyV-DNAemia. However, anti-st levels were significantly higher at T0 in KTR-cases able to clear at T6 or T12. In 34 KTR-cases with deep genome sequencing, BKPyV-gtI was predominant, and anti-st1 and st1-neutralizing antibodies were significantly lower at T0 than in KTR-controls. Thus, BKPyV st-specific antibody levels at transplantation might reflect gt/st-BKPyV-specific immunity clearing or preventing BKPyV-DNAemia in KTR-cases or KTR-controls, respectively. Accordingly, active or passive immunization may be most efficient pretransplant or early post-transplant., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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5. Transient biopsy-proven progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) in an elderly woman without known immunodeficiency: a case report.
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Ingebrigtsen SG, Myrmel KS, Henriksen S, Wikran GC, Herder M, Tylden GD, Hirsch HH, and Rinaldo CH
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- Humans, Female, Aged, Biopsy methods, Magnetic Resonance Imaging, Brain pathology, Brain diagnostic imaging, JC Virus, Leukoencephalopathy, Progressive Multifocal diagnostic imaging, Leukoencephalopathy, Progressive Multifocal diagnosis, Immune Reconstitution Inflammatory Syndrome diagnosis
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Background: Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic brain disease caused by lytic JC polyomavirus (JCPyV) replication in oligodendrocytes. Although JCPyV infection is common in the general population, PML almost exclusively occurs in patients immunocompromised due to untreated HIV/AIDS, haematological malignancies, primary immunodeficiencies, solid organ transplantation, or immunomodulatory treatment of autoimmune diseases. There is no effective antiviral treatment, and recovery depends on immune reconstitution. Paradoxically, initiation of antiretroviral therapy for HIV/AIDS or interruption of immunomodulating treatment can worsen the clinical manifestations due to immune reconstitution inflammatory syndrome (IRIS). Here, we report an unusual case of spontaneous IRIS in a 76-year-old immunocompetent woman, unmasking PML and leading to unexpected recovery., Case Presentation: The patient was admitted to the hospital due to psychosis, speech impairment, and behavioral changes over the last three months. She had previously been healthy, except for a cerebellar stroke secondary to paroxysmal atrial fibrillation. Magnetic resonance imaging (MRI) revealed multiple contrast-enhancing white matter lesions suspicious of cancer metastases. Due to suspicion of edema, dexamethasone was administered, and the patient was released while waiting for a stereotactic brain biopsy. Eight days later, she suffered tonic seizures and was readmitted. Intravenous levetiracetam gave rapid effect, but the patient was paranoid and non-cooperative, and dexamethasone was unintentionally discontinued. Ten days later, the brain biopsy revealed demyelination, abundant perivascular T cells, macrophages, and scattered JCPyV-infected oligodendrocytes, rendering the diagnosis of PML-IRIS. The cerebrospinal fluid contained low amounts of JCPyV-DNA, and plasma contained high levels of anti-JCPyV immunoglobulin G. Despite extensive immunological testing, no evidence of immunodeficiency was found. The patient gradually recovered clinically and radiologically. More than 19 months after diagnosis, the patient has only a slight impairment in language and behavior., Conclusions: An apparently immunocompetent elderly person developed clinically symptomatic PML, which spontaneously resolved with symptoms and signs of IRIS. The atypical MRI lesions with contrast enhancement and the lack of known immunological risk factors for PML delayed the diagnosis, eventually proved by biopsy. PML and PML-IRIS should be considered in the differential diagnosis of patients presenting CNS symptoms and focal lesions with contrast enhancement on MRI., (© 2024. The Author(s).)
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- 2024
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6. Single-cell RNA-sequencing of BK polyomavirus replication in primary human renal proximal tubular epithelial cells identifies specific transcriptome signatures and a novel mitochondrial stress pattern.
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Weissbach FH, Follonier OM, Schmid S, Leuzinger K, Schmid M, and Hirsch HH
- Abstract
BK polyomavirus (BKPyV) contributes to premature renal failure in 10%-20% of kidney transplant recipients. Current treatment relies on reducing immunosuppression to regain BKPyV-specific immune control. Subsequently, declining allograft function may result from persisting viral cytopathology, BKPyV-specific immune reconstitution, or alloimmunity/rejection, all being poorly distinguishable by current histological or molecular approaches. To reduce the complexity encountered in BKPyV-replicating kidneys, we analyzed differentially expressed genes (DEGs) in primary human renal proximal tubular epithelial cells at 24 and 48 h post-infection (hpi) using single-cell RNA-sequencing (10x-Genomics-3´ kit). At 24 hpi, viral transcript reads predominantly mapped to the early viral gene region ( EVGR ) and shifted to >100-fold higher late viral gene region ( LVGR ) levels at 48 hpi, matching the sequential bi-directional viral protein expression from the circular double-stranded BKPyV-DNA genome. Besides expected coverage "hills" at viral 3´-poly-A sites, unexpected "spike" and "pulse" reads resulted from off-target TSO priming. "Spike" and "pulse" patterns were rare for the mostly unidirectional reads mapping to the circular mitochondrial genome. Bioinformatic curation removed "spikes" and "pulses" and reclassified 10% of DEGs in renal proximal tubular epithelial cells (RPTECs). Up-regulated gene ontologies included S and G2/M phase, double-stranded DNA repair, proximal tubulopathy, and renal tubular dysfunction, whereas allograft rejection, antigen presentation, innate immunity, translation, and autophagy were down-regulated. BKPyV- LVGR expression induced a novel mitochondrial cell stress pattern consisting of discordant up-regulation and down-regulation of mitochondria-encoded and nucleus-encoded mitochondrial genes, respectively. We explored which top-scoring gene sets of late-phase BKPyV-replicating RPTECs can identify BKPyV-associated nephropathy in kidney transplant biopsies. The results should facilitate distinguishing BKPyV-associated pathology from other entities in kidney transplant biopsies.IMPORTANCEBK polyomavirus (BKPyV) infects more than 90% of the general population and then persists in the reno-urinary tract. Subsequently, low-level urinary shedding is seen in 10% of healthy BKPyV-seropositive persons, indicating that BKPyV replication occurs despite the presence of virus-specific cellular and humoral immunity. Notably, transplantation of donor kidneys with low-level BKPyV replication is a risk factor for progression to high-level BKPyV viruria, new-onset BKPyV-DNAemia and biopsy-proven BKPyV nephropathy. Here, we identify a short list of robust up- and down-regulated nucleus-encoded differentially expressed genes potentially allowing to discriminate viral from allograft immune damage. By carefully curating viral and mitochondrial transcriptomes, we identify a novel virus-associated mitochondrial stress pattern of up-regulated mitochondria-encoded and down-regulated nucleus-encoded mitochondrial transcripts which heralds the BKPyV-agnoprotein-mediated immune escape by breakdown of the mitochondrial membrane potential and network and mitophagy. The results may prove useful when assessing the role of BKPyV replication in kidney transplant patients with suspected acute rejection and/or BKPyV nephropathy.
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- 2024
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7. Comprehensive Herpesviruses Antiviral drug Resistance Mutation Database (CHARMD).
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Tilloy V, Díaz-González D, Laplace L, Bisserier E, Chou S, Rawlinson WD, Boivin G, Baldanti F, Lazzarotto T, Andrei G, Hirsch HH, Marcos MÁ, Michel D, Hantz S, and Alain S
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- Humans, Herpesviridae genetics, Herpesviridae drug effects, Databases, Genetic, Genotype, Herpesviridae Infections virology, Drug Resistance, Viral genetics, Antiviral Agents pharmacology, Mutation
- Abstract
A comprehensive and accessible Herpesvirus drug resistance database was designed to serve as an international reference for diagnosis and clinical studies. This database available at https://www.unilim.fr/cnr-herpesvirus/outils/codexmv/includes both resistance-related mutations and natural polymorphisms. Initially designed for human cytomegalovirus, it will be expanded to include herpes simplex and varicella-zoster viruses. Newly published mutations and new mutations reported by users or collaborating expert laboratories will be reviewed by an international committee of reference laboratories before inclusion in the database. Coupled with the Herpesvirus Sequence Analysis tool (HSA) mutation reports from NGS or Sanger sequences, it will be an open source for researchers in the field of Herpesviruses. We hope to fill this unmet need for the development and standardization of resistance genotyping., Competing Interests: Declaration of competing interest This comprehensive Antiviral Resistance database was developed by S. Alain, V. Tilloy, D. Díaz-González and S. Hantz at Limoges hospital as part of the ‘Center National de Référence des Herpèsvirus’ tasks. The CHARMD database and the HSA tool, whose creators are among the authors of the article, are currently being registered with the French Agency for the Protection of Programs., (Copyright © 2024. Published by Elsevier B.V.)
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- 2024
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8. A Hitchhiker's Guide to the BK Galaxy.
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Hirsch HH and Kotton CN
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2024
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9. Transcriptional profile of Mycobacterium tuberculosis infection in people living with HIV.
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Tepekule B, Jörimann L, Schenkel CD, Opitz L, Tschumi J, Wolfensberger R, Neumann K, Kusejko K, Zeeb M, Boeck L, Kälin M, Notter J, Furrer H, Hoffmann M, Hirsch HH, Calmy A, Cavassini M, Labhardt ND, Bernasconi E, Oesch G, Metzner KJ, Braun DL, Günthard HF, Kouyos RD, Duffy F, and Nemeth J
- Abstract
In people with HIV-1 (PWH), Mycobacterium tuberculosis (MTB) infection poses a significant threat. While active tuberculosis (TB) accelerates immunodeficiency, the interaction between MTB and HIV-1 during asymptomatic phases remains unclear. Analysis of peripheral blood mononuclear cells (PBMC) transcriptomic profiles in PWH, with and without controlled viral loads, revealed distinct clustering in MTB-infected individuals. Functional annotation identified alterations in IL-6, TNF, and KRAS pathways. Notably, MTB-related genes displayed an inverse correlation with HIV-1 viremia, at both individual and signature score levels. These findings suggest that MTB infection in PWH induces a shift in immune system activation, inversely related to HIV-1 viral load. These results may explain the observed enhanced antiretroviral control in MTB-infected PWH. This study highlights the complex interplay between MTB and HIV-1, emphasizing the importance of understanding their interaction for managing co-infections in this population., Competing Interests: A.C. received grants from Merck Sharp & Dohme (MSD), ViiV Healthcare, and Gilead Sciences for unrelated research. R.D.K. received grants from Gilead Sciences and National Institutes of Health (NIH) for unrelated research. D.L.B. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Pfizer, and AstraZeneca. D.L.B. received honoraria for presentations from Gilead Sciences and Merck. E.B. received grants from MSD for unrelated research. E.B. received payments for travel reimbursement from ViiV, MSD, Gilead Sciences, Pfizer, and Abbvie. E.B. received honoraria for working on the advisory board of ViiV, MSD, Pfizer, Gilead Sciences, AstraZeneca, and Ely Lilly. H.H.H. received honoraria for working on the advisory board of AiCuris, Merck, Vera Dx, and Molecular Partners. H.H.H. received honoraria for presentations from Merck, Gilead Sciences, Biotest, and Vera Dx. J.N. received honoraria for presentations from Oxford Immunotec, Gilead and ViiV. H.FG. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Janssen, Johnson and Johnson, Novartis, and GlaxoSmithKline (GSK). H.F.G. received payments for travel reimbursements from Gilead Sciences. H.F.G. received grants from NIH, Yvonne Jacob Foundation, and Gilead Sciences., (© 2024 The Author(s).)
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- 2024
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10. Circulating HBV RNA and Hepatitis B Core-Related Antigen Trajectories in Persons With HIV/HBV Coinfection and Hepatitis B Surface Antigen Loss During Tenofovir Therapy.
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Begré L, Boyd A, Plissonnier ML, Testoni B, Salazar-Vizcaya L, Suter-Riniker F, Scholtès C, Béguelin C, Rockstroh JK, Günthard HF, Calmy A, Cavassini M, Hirsch HH, Schmid P, Bernasconi E, Levrero M, Wandeler G, Zoulim F, and Rauch A
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- Humans, Male, Female, Adult, Middle Aged, Hepatitis B drug therapy, Hepatitis B blood, Hepatitis B virology, Anti-HIV Agents therapeutic use, Cohort Studies, Switzerland epidemiology, Viral Load, Hepatitis B, Chronic drug therapy, Hepatitis B, Chronic blood, Hepatitis B, Chronic virology, Hepatitis B, Chronic complications, DNA, Viral blood, Tenofovir therapeutic use, HIV Infections drug therapy, HIV Infections blood, HIV Infections complications, HIV Infections virology, Hepatitis B Surface Antigens blood, RNA, Viral blood, Hepatitis B virus genetics, Hepatitis B Core Antigens blood, Coinfection drug therapy, Coinfection virology
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Background: We evaluated long-term trajectories of circulating hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) in persons with and without hepatitis B surface antigen (HBsAg) loss during tenofovir therapy in the Swiss HIV Cohort Study., Methods: We included 29 persons with HIV with HBsAg loss and 29 matched persons with HIV without HBsAg loss. We compared HBV RNA and HBcrAg decline and assessed the cumulative proportions with undetectable HBV RNA and HBcrAg levels during tenofovir therapy using Kaplan-Meier estimates., Results: HBsAg loss occurred after a median of 4 years (IQR, 1-8). All participants with HBsAg loss achieved suppressed HBV DNA and undetectable HBV RNA preceding undetectable quantitative HBsAg levels, whereas 79% achieved negative HBcrAg. In comparison, 79% of participants without HBsAg loss achieved undetectable HBV-RNA and 48% negative HBcrAg. After 2 years of tenofovir therapy, an HBV RNA decline ≥1 log10 copies/mL had 100% sensitivity and 36.4% specificity for HBsAg loss, whereas an HBcrAg decline ≥1 log10 U/mL had 91.0% sensitivity and 64.5% specificity., Conclusions: HBV RNA suppression preceded undetectable quantitative HBsAg levels and had high sensitivity but low specificity for HBsAg loss during tenofovir therapy in persons with HIV. HBcrAg remained detectable in approximately 20% of persons with HBsAg loss and 50% of persons without HBsAg loss., Competing Interests: Potential conflicts of interest. L. B. reports support for travel and conference participation from the CROI Foundation and the SAFE-ID Foundation. A. B. has received speaker honoraria from Gilead unrelated to this work. M.-L. P. reported support for the present article from the CirB-RNA-RHU program paid to her institution. B. T. has received honoraria for lectures from Gilead Sciences France, Hopital Vall D’Hebron, and the Belgian Association for the Study of the Liver and payment for expert testimony and travel support from the International Hepatology Education Program. L. S.-V. has received honoraria for consulting from Gilead paid to her institution and unrelated to this work. F. S.-R. reports no potential conflicts. C. S. received speaker honoraria and travel support from Gilead and a grant from Roche Diagnostics paid to her institution and unrelated to this work. C. B. has received advisory board membership fees from Gilead paid to his institution. J. K. R. has received honoraria for consulting or speaking at educational events from Boehringer, Gilead, Merck, Janssen, and ViiV. H. F. G. has received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck, Johnson & Johnson, Janssen, GSK, Novartis, and ViiV Healthcare; and grants from the Swiss National Science Foundation, the Bill & Melinda Gates Foundation, the Yvonne Jacob Foundation, Gilead, ViiV, and the National Institutes of Health. A. C. reported unrestricted educational grants from ViiV, Gilead, and MSD and industry-sponsored clinical trials at her HIV unit. M. C.'s institution received research grants from Gilead, MSD, and ViiV and financial compensation for expert opinion given to Gilead, MSD, and ViiV. H. H. H. received grant support from Moderna paid to his institution and honoraria for consulting or speaking at educational events from AICuris, Allovir, Moderna, VeraTx, Roche, Takeda, Biotest, and Gilead. P.S.'s institution has received travel grants and congress/advisory fees from Gilead and ViiV unrelated to this work. The institution of E. B. received grants from MSD; consulting fees from Moderna; speaker fees from Pfizer AG Switzerland; and payments for the participation of E. B. to advisory boards or travel grants from Gilead Sciences, ViiV Healthcare, MSD, Pfizer AG Switzerland, Moderna, Astra Zeneca, Eli Lilly, and Abbvie. M. L. has received lecture and presentation fees from Abbvie and Gilead and coverage and reimbursement of travel expenses from Abbvie, Gilead, Inventiva, Madrigal, and MSD. G. W. received unrestricted research grants from Gilead Sciences and Roche Diagnostics and lecture/advisory board membership fees from Gilead Sciences, MSD, and ViiV Healthcare, all paid to his institution. F. Z. has received speaker fees from Gilead; consulting fees from Aligos, Assembly, Blue Jay, and GSK; and research grants through INSERM from Assembly, Beam, Blue Jay, and Janssen. A. R. reports support to his institution for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer, and Moderna and an investigator-initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to A. R. personally, and all remuneration was provided outside the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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11. Infectious disease events in people with HIV receiving kidney transplantation: Analysis of the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study.
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Kusejko K, Kouyos RD, Bernasconi E, Boggian K, Braun DL, Calmy A, Cavassini M, van Delden C, Furrer H, Garzoni C, Hirsch HH, Hirzel C, Manuel O, Schmid P, Khanna N, Haidar F, Bonani M, Golshayan D, Dickenmann M, Sidler D, Schnyder A, Mueller NJ, Günthard HF, and Schreiber PW
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- Humans, Male, Female, Switzerland epidemiology, Middle Aged, Adult, Cohort Studies, Risk Factors, Communicable Diseases epidemiology, Communicable Diseases etiology, HIV Infections complications, HIV Infections drug therapy, Kidney Transplantation adverse effects
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Background: Since the implementation of universal antiretroviral therapy, kidney transplantation (K-Tx) has become a valuable option for treatment of end-stage kidney disease for people with HIV (PWH) with similar patient and graft survival as compared to HIV-uninfected patients. Little is known about the hazards and manifestations of infectious disease (ID) events occurring in kidney transplant recipients with HIV., Methods: Using linked information collected in the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), we described in-depth demographical and clinical characteristics of PWH who received a K-Tx since 2008. Further, we performed recurrent time to event analyses to understand whether HIV was an independent risk factor for ID events., Results: Overall, 24 PWH with 57 ID events were included in this study (100% match of SHCS to STCS). Of these, 17 (70.8%) patients had at least one ID event: 22 (38.6%) viral (HIV not counted), 18 (31.6%) bacterial, one (1.8%) fungal and 16 (28.1%) probable infections. Most ID events affected the respiratory tract (25, 37.3%) or the urinary tract (13, 19.4%). Pathogen types and infection sites were similar in PWH and a matched control group of HIV-uninfected patients. HIV was not an independent risk factor for ID events (adjusted hazard ratio 0.94, p = 0.9)., Conclusion: By linking data from two large national Swiss cohorts, we provided in-depth information on ID events in PWH receiving a K-Tx in Switzerland. HIV infection was not associated with an increased hazard for ID events after K-Tx., (© 2024. The Author(s).)
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- 2024
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12. Risk of cellular or antibody-mediated rejection in pediatric kidney transplant recipients with BK polyomavirus replication-an international CERTAIN registry study.
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Fichtner A, Schmidt J, Süsal C, Carraro A, Oh J, Zirngibl M, König S, Guzzo I, Weber LT, Awan A, Krupka K, Schnitzler P, Hirsch HH, Tönshoff B, and Höcker B
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Background: In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection., Methods: This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR., Results: BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013)., Conclusions: These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended., (© 2024. The Author(s).)
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- 2024
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13. Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.
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Fernbach S, Mair NK, Abela IA, Groen K, Kuratli R, Lork M, Thorball CW, Bernasconi E, Filippidis P, Leuzinger K, Notter J, Rauch A, Hirsch HH, Huber M, Günthard HF, Fellay J, Kouyos RD, and Hale BG
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- Humans, Middle Aged, Male, Female, Adult, Aged, SARS-CoV-2 immunology, HIV Infections immunology, Interferon-alpha immunology, Retrospective Studies, Autoantibodies immunology, Interferon Type I immunology, COVID-19 immunology, Antibodies, Neutralizing immunology
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Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency., (© 2024 Fernbach et al.)
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- 2024
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14. Reducing Immunosuppression for BK Polyomavirus-What to do About Corticosteroids?
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Hirsch HH, Pape L, Tedesco Silva H, and Kotton CN
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- Humans, Kidney Transplantation, Treatment Outcome, Risk Factors, BK Virus immunology, BK Virus pathogenicity, Polyomavirus Infections immunology, Polyomavirus Infections virology, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Tumor Virus Infections immunology, Tumor Virus Infections virology, Adrenal Cortex Hormones therapeutic use
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Competing Interests: The authors declare no funding or conflicts of interest.
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- 2024
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15. The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation.
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Kotton CN, Kamar N, Wojciechowski D, Eder M, Hopfer H, Randhawa P, Sester M, Comoli P, Tedesco Silva H, Knoll G, Brennan DC, Trofe-Clark J, Pape L, Axelrod D, Kiberd B, Wong G, and Hirsch HH
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- Humans, Antiviral Agents therapeutic use, Risk Factors, Treatment Outcome, BK Virus immunology, BK Virus pathogenicity, Consensus, Immunosuppressive Agents therapeutic use, Immunosuppressive Agents adverse effects, Kidney Transplantation adverse effects, Polyomavirus Infections diagnosis, Polyomavirus Infections immunology, Polyomavirus Infections virology, Tumor Virus Infections immunology, Tumor Virus Infections diagnosis, Tumor Virus Infections virology, Practice Guidelines as Topic
- Abstract
BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials., Competing Interests: C.N.K. received grants from Biohope and funding for serving on scientific advisory boards for Roche Diagnostics. N.K. received consulting fees, honoraria, and travel support from Astellas, AstraZeneca, Biotest, CSL Behring, Chiesi, Gilead, Hansa, Merck, Sharp and Dohme, Glasgow Smith Kline, Neovii, Novartis Pharma, Roche, Sanofi, Sandoz, and Takeda. P.R. received consulting fees from Allovir. M.S. received consulting fees from Merck, Sharp and Dohme, Moderna, and Biotest and honoraria from Biotest, Novartis, Merck, Sharp and Dohme, Takeda, and Qiagen. P.C. received honoraria from Atara Bio and Pierre Fabre Pharma. H.T.S. received grants from Biohope, Merck Sharp and Dohme, Natera, Novartis, and Takeda; honoraria from Alexion, CareDx, EMS Pharmaceuticals, Natera, and Takeda; and consulting fees and travel support from Takeda. D.C.B. received grants from CareDx and VeraTherapeutics and consulting fees from CareDx, Medeor Therapeutics, Natera, Sanofi, and Vera Therapeutics. L.P. received grants from Alexion, Chiesi, and Novartis; consulting fees from Alnylam and Chiesi; and travel support from Alexion. H.H.H. received consulting fees from AICuris, Allovir, Moderna, VeraTX, and Roche and honoraria from VeraTX, Takeda, Biotest, and Gilead. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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16. Secondary attack rate following on-site isolation of patients with suspected COVID-19 in multiple-bed rooms.
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Ragozzino S, Kuehl R, Leuzinger K, Schläpfer P, Urwyler P, Durovic A, Zingg S, von Rotz M, Battegay M, Widmer AF, Hirsch HH, Bassetti S, and Tschudin-Sutter S
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- Humans, Female, Male, Switzerland epidemiology, Middle Aged, Aged, Adult, Aged, 80 and over, Hospitals, University, COVID-19 transmission, COVID-19 epidemiology, COVID-19 diagnosis, Patient Isolation, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, Patients' Rooms
- Abstract
The implementation of isolation precautions for patients with suspected Coronavirus Disease 2019 (COVID-19) and pending test results is resource intensive. Due to the limited availability of single-bed rooms at our institution, we isolated patients with suspected COVID-19 together with patients without suspected COVID-19 on-site in multiple-bed rooms until SARS-CoV-2-test results were available. We evaluated the likelihood of SARS-CoV-2 transmission to individuals sharing the room with patients isolated on-site. This observational study was performed at the University Hospital Basel, Switzerland, from 03/20 - 11/20. Secondary attack rates were compared between patients hospitalized in multiple-bed rooms and exposed to individuals subjected to on-site isolation precautions (on-site isolation group), and patients exposed to individuals initially not identified as having COVID-19, and not placed under isolation precautions until the diagnosis was suspected (control group). Transmission events were confirmed by whole-genome sequencing. Among 1,218 patients with suspected COVID-19, 67 (5.5%) tested positive for SARS-CoV-2. Of these, 21 were isolated on-site potentially exposing 27 patients sharing the same room. Median contact time was 12 h (interquartile range 7-18 h). SARS-CoV-2 transmission was identified in none of the patients in the on-site isolation group vs. 10/63 (15.9%) in the control group (p = 0.03). Isolation on-site of suspected COVID-19-patients in multiple-bed rooms avoided single-room occupancy and subsequent in-hospital relocation for many patients without confirmed SARS-CoV-2-infection. The absence of secondary transmission among the exposed patients in the on-site isolation group allows for assessment of the risk/benefit ratio of this strategy given the limitation of a small sample size., (© 2024. The Author(s).)
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- 2024
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17. Anti-SARS-CoV-2 total immunoglobulin and neutralising antibody responses in healthy blood donors throughout the COVID-19 pandemic: a longitudinal observational study.
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Gütlin Y, Albertos Torres D, Gensch A, Schlotterbeck AK, Stöger L, Heller S, Infanti L, Barut GT, Thiel V, Leuzinger K, Hirsch HH, Buser A, and Egli A
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- Humans, Longitudinal Studies, Male, Female, Adult, Middle Aged, Neutralization Tests, Switzerland, Enzyme-Linked Immunosorbent Assay, Spike Glycoprotein, Coronavirus immunology, Aged, Adolescent, Young Adult, COVID-19 immunology, COVID-19 prevention & control, Blood Donors statistics & numerical data, SARS-CoV-2 immunology, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antibodies, Viral immunology
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Introduction: Quantifying antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neutralising antibodies may help to understand protection at the individual and population levels. Determination of neutralising antibodies using classical virus neutralisation tests (VNT) is considered the gold standard, but they are costly and time-intensive. Enzyme-linked immunosorbent assay (ELISA)-based surrogate VNTs (sVNT) or anti-SARS-CoV-2 spike protein receptor binding domain immunoglobulins (anti-S-RBD Ig) may be suitable alternatives to VNTs. We aimed to (a) explore the correlations between anti-S-RBD Ig, VNT, and sVNT measurements and (b) describe humoral immunity against SARS-CoV-2 after vaccination, natural infection, and vaccine breakthrough infection in healthy blood donors., Methods: We measured total anti-SARS-CoV-2 Ig in 5714 serum samples from 2748 healthy individuals visiting the Swiss Red Cross Blood Donation Centre in Basel from 03/2020 to 04/2022. We used the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche) against the N- and S-receptor binding domain (RBD) proteins. In a subset of 548 samples from 123 donors, we conducted sVNTs against the Wuhan wild-type SARS-CoV-2 (SARS-CoV-2 Neutralizing Antibodies Detection Kit; Adipogen™). In 100 samples from 40 donors, we correlated sVNT and VNTs against the wild-type (D614G WU1) virus. Surveys were sent to the blood donors to collect data on their SARS-CoV-2 infection and vaccination status. Using this data, donors were categorised as "vaccination only", "infection before vaccination", "post-vaccine breakthrough infection", and "natural infection only"., Results: Our longitudinal observation study cohort consisted of 50.7% males with a median age of 31 years (range 18-75 y). Anti-SARS-CoV-2 N protein positivity rates per month indicate 57.1% (88/154) of the cohort was infected up to 04/2022. No differences in seropositivity were found between sexes, age groups, blood types (AB0 or RhD), and cytomegalovirus serostatus. We observed a high correlation between anti-S-RBD Ig and inhibition percentage (Spearman's ρ = 0.92, Kendall's τ = 0.77, p <0.0001). We determined the sensitivity and specificity for the manufacturers' thresholds for detecting virus-neutralising effects and computed the "best" cut-off based on our real-world data. We categorised 722/1138 (63.5%) donors as vaccination only (82.3%), post-vaccine breakthrough infection (7.8%), infection before vaccination (5.8%), and natural infection only (4.2%). We observed a lower inhibition percentage in the natural infection-only group than in all other vaccinated groups. The infection before vaccination group had higher anti-S-RBD Ig titres after the first vaccine dose than the other vaccinated groups., Conclusion: In total, 57.1% of healthy blood donors were infected with SARS-CoV-2, but natural infection without evidence of vaccination seems to result in substantially lower neutralising antibody levels. An estimate of antibody neutralisation may be helpful to assess reinfection risk. Total anti-S-RBD Ig correlates with surrogate virus neutralisation test results, a surrogate for neutralisation; therefore, we suggest that total anti-S-RBD Ig may estimate the level of neutralising antibodies. The threshold for protection from an unfavourable clinical outcome must be evaluated in prospective clinical cohorts.
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- 2024
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18. Comparative evaluation of Anyplex II HPV28 and Allplex HPV28 molecular assays for human papillomavirus detection and genotyping in anogenital cancer screening.
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Naegele K, Bubendorf L, Hirsch HH, and Leuzinger K
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- Humans, Female, Male, Middle Aged, Adult, Aged, Prospective Studies, Molecular Diagnostic Techniques methods, DNA, Viral genetics, Genotyping Techniques methods, Young Adult, Sensitivity and Specificity, Anus Neoplasms virology, Anus Neoplasms diagnosis, Human Papillomavirus Viruses, Alphapapillomavirus, Papillomavirus Infections virology, Papillomavirus Infections diagnosis, Papillomaviridae genetics, Papillomaviridae classification, Papillomaviridae isolation & purification, Genotype, Early Detection of Cancer methods
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Persistent infection with high-risk human papillomavirus (HPV) is recognized as the main cause for the development of anogenital cancers. This study prospectively evaluated the diagnostic performance of the novel Allplex-HPV28 assay with the Anyplex-II-HPV28 to detect and genotype HPV in 234 consecutive swabs and 32 biopsies of the anogenital tract from 265 patients with atypical findings in cytomorphological screening. Agreement in HPV-DNA detection between the Anyplex-II and Allplex-HPV28 assays was 99%. There was a notable diversity in the HPV-virome, with the most prevalent high-risk HPV types being 16, 53, 66, and 68. The agreement rates for detecting these genotypes exceeded 93% between the Anyplex-II and Allplex-HPV28 assays. Discrepancies in test results were solely noted for Anyplex-II-HPV28 results with a low signal intensity of "+", and for Allplex-HPV28 results with cycle thresholds of ≥36. The semi-quantitative analysis of HPV-DNA loads showed significant agreement between the Anyplex-II-HPV28 and Allplex-HPV28 assays (p < 0.001). Furthermore, HPV-DNA detection rates and mean HPV-DNA loads significantly correlated with the grade of abnormal changes identified in cytopathological assessment, being highest in cases of HSIL, condyloma accuminatum, and squamous cell carcinoma. Overall agreement rates for detecting specific HPV-types among the Anyplex-II and Allplex-HPV28 assays exceeded 99.5% in cases of atypical squamous cells, condyloma accuminatum, and squamous cell carcinoma. The novel Allplex-HPV28 assay shows good diagnostic performance in detecting and genotyping HPV commonly associated with anogenital cancers. Consequently, this assay could offer substantial potential for incorporation into future molecular screening programs for anogenital cancers in clinical settings., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)
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- 2024
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19. Structural implications of BK polyomavirus sequence variations in the major viral capsid protein Vp1 and large T-antigen: a computational study.
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Durairaj J, Follonier OM, Leuzinger K, Alexander LT, Wilhelm M, Pereira J, Hillenbrand CA, Weissbach FH, Schwede T, and Hirsch HH
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BK polyomavirus (BKPyV) is a double-stranded DNA virus causing nephropathy, hemorrhagic cystitis, and urothelial cancer in transplant patients. The BKPyV-encoded capsid protein Vp1 and large T-antigen (LTag) are key targets of neutralizing antibodies and cytotoxic T-cells, respectively. Our single-center data suggested that variability in Vp1 and LTag may contribute to failing BKPyV-specific immune control and impact vaccine design. We, therefore, analyzed all available entries in GenBank (1516 VP1 ; 742 LTAG ) and explored potential structural effects using computational approaches. BKPyV-genotype (gt)1 was found in 71.18% of entries, followed by BKPyV-gt4 (19.26%), BKPyV-gt2 (8.11%), and BKPyV-gt3 (1.45%), but rates differed according to country and specimen type. Vp1-mutations matched a serotype different than the assigned one or were serotype-independent in 43%, 18% affected more than one amino acid. Notable Vp1-mutations altered antibody-binding domains, interactions with sialic acid receptors, or were predicted to change conformation. LTag-sequences were more conserved, with only 16 mutations detectable in more than one entry and without significant effects on LTag-structure or interaction domains. However, LTag changes were predicted to affect HLA-class I presentation of immunodominant 9mers to cytotoxic T-cells. These global data strengthen single center observations and specifically our earlier findings revealing mutant 9mer epitopes conferring immune escape from HLA-I cytotoxic T cells. We conclude that variability of BKPyV-Vp1 and LTag may have important implications for diagnostic assays assessing BKPyV-specific immune control and for vaccine design., Importance: Type and rate of amino acid variations in BKPyV may provide important insights into BKPyV diversity in human populations and an important step toward defining determinants of BKPyV-specific immunity needed to protect vulnerable patients from BKPyV diseases. Our analysis of BKPyV sequences obtained from human specimens reveals an unexpectedly high genetic variability for this double-stranded DNA virus that strongly relies on host cell DNA replication machinery with its proof reading and error correction mechanisms. BKPyV variability and immune escape should be taken into account when designing further approaches to antivirals, monoclonal antibodies, and vaccines for patients at risk of BKPyV diseases., Competing Interests: The authors declare no conflict of interest.
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- 2024
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20. Impact of Swabbing Location, Self-Swabbing, and Food Intake on SARS-CoV-2 RNA Detection.
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Dräger S, Bruni F, Bernasconi M, Hammann-Hänni A, Jirasko V, Tanno A, Blickenstorfer Y, Leuzinger K, Hirsch HH, and Osthoff M
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This study compared SARS-CoV-2 RNA loads at different anatomical sites, and the impact of self-swabbing and food intake. Adult symptomatic patients with SARS-CoV-2 or non-SARS-CoV-2 respiratory tract infection were included between 2021 and 2022. Patients performed a nasal and buccal swab before a professionally collected nasopharyngeal/oropharyngeal swab (NOPS). Buccal swabs were collected fasting and after breakfast in a subgroup of patients. SARS-CoV-2 RNA loads were determined by nucleic acid testing. Swabbing convenience was evaluated using a survey. The median age of 199 patients was 54 years (interquartile range 38-68); 42% were female and 52% tested positive for SARS-CoV-2. The majority of patients (70%) were hospitalized. The mean SARS-CoV-2 RNA load was 6.6 log
10 copies/mL (standard deviation (SD), ±1.5), 5.6 log10 copies/mL (SD ± 1.9), and 3.4 log10 copies/mL (SD ± 1.9) in the professionally collected NOPS, and self-collected nasal and buccal swabs, respectively ( p < 0.0001). Sensitivity was 96.1% (95% CI 90.4-98.9) and 75.3% (95% CI 63.9-81.8) for the nasal and buccal swabs, respectively. After food intake, SARS-CoV-2 RNA load decreased ( p = 0.0006). Buccal swabbing was the preferred sampling procedure for the patients. In conclusion, NOPS yielded the highest SARS-CoV-2 RNA loads. Nasal self-swabbing emerged as a reliable alternative in contrast to buccal swabs. If buccal swabs are used, they should be performed before food intake.- Published
- 2024
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21. Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity.
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Tepekule Mueller B, Joerimann L, Schenkel CD, Opitz L, Tschumi J, Wolfensberger R, Neumann K, Kusejko K, Zeeb M, Boeck L, Kaelin M, Notter J, Furrer H, Hoffmann M, Hirsch HH, Calmy A, Cavassini M, Labhardt ND, Bernasconi E, Metzner KJ, Braun DL, Guenthard HF, Kouyos RD, Duffy F, and Nemeth J
- Abstract
Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.
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- 2024
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22. Clinical trials for treatment of respiratory viral infections in recipients of haematopoietic cell transplantation and cellular therapies: are we on the right path to the finish line?
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Sassine J, Hirsch HH, and Chemaly RF
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- Humans, Immunocompromised Host, Clinical Trials as Topic, Hematopoietic Stem Cell Transplantation adverse effects, Respiratory Tract Infections therapy, Virus Diseases prevention & control, Virus Diseases drug therapy
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- 2024
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23. Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.
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Manuel O, Laager M, Hirzel C, Neofytos D, Walti LN, Hoenger G, Binet I, Schnyder A, Stampf S, Koller M, Mombelli M, Kim MJ, Hoffmann M, Koenig K, Hess C, Burgener AV, Cippà PE, Hübel K, Mueller TF, Sidler D, Dahdal S, Suter-Riniker F, Villard J, Zbinden A, Pantaleo G, Semmo N, Hadaya K, Enríquez N, Meylan PR, Froissart M, Golshayan D, Fehr T, Huynh-Do U, Pascual M, van Delden C, Hirsch HH, Jüni P, and Mueller NJ
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- Humans, Cytomegalovirus, Antiviral Agents therapeutic use, Monitoring, Immunologic, Transplant Recipients, Ganciclovir therapeutic use, Cytomegalovirus Infections diagnosis, Organ Transplantation adverse effects
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Background: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation., Methods: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus., Results: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001)., Conclusions: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection., Clinical Trials Registration: NCT02538172., Competing Interests: Potential conflicts of interest. O. M. reports research grants from Lophius Biosciences (acquired by Mikrogen), the Novartis Foundation, and the Swiss Transplant Cohort Study; participation on a data and safety monitoring board for Syneos and in advisory boards of MSD, Biotest, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, paid to their institution. H. H. H. reports grants from Moderna paid to their institution; consulting fees from AiCuris, Allovir, Moderna, VeraTX, and Roche; and honoraria from VeraTX, Takeda, Biotest, and Gilead. P. J. reports serving as an unpaid member of the steering group of a trial funded by Terumo and research grants to their institution from Appili Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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24. Do Infectious Diseases After Kidney Retransplantation Differ From Those After First Kidney Transplantation?
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Kusejko K, Neofytos D, van Delden C, Hirsch HH, Meylan P, Boggian K, Hirzel C, Garzoni C, Sidler D, Schnyder A, Schaub S, Golshayan D, Haidar F, Bonani M, Kouyos RD, Mueller NJ, and Schreiber PW
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Background: Infectious diseases (IDs) are highly relevant after solid organ transplantation in terms of morbidity and mortality, being among the most common causes of death. Patients undergoing kidney retransplantation (re-K-Tx) have been already receiving immunosuppressive therapy over a prolonged period, potentially facilitating subsequent infections. Comparing ID events after re-K-Tx and first kidney transplantation (f-K-Tx) can delineate patterns and risks of ID events associated with prolonged immunosuppression., Methods: We included adult patients with records on f-K-Tx and re-K-Tx in the Swiss Transplant Cohort Study. We analyzed ID events after f-K-Tx and re-K-Tx within the same patients and compared infection rates, causative pathogens, and infection sites. Recurrent time-to-event analyses were performed for comparison of infection rates., Results: A total of 59 patients with a median age of 47 years (range, 18-73) were included. Overall, 312 ID events in 52 patients occurred. In multivariable recurrent event modeling, the rate of ID events was significantly lower after re-K-Tx (hazard ratio, 0.70; P = .02). More bacterial (68.9% vs 60.4%) and fungal (4.0% vs 1.1%) infections were observed after f-K-Tx but fewer viral infections (27.0% vs 38.5%) as compared with re-K-Tx ( P = .11). After f-K-Tx, urinary and gastrointestinal tract infections were more frequent; after re-K-Tx, respiratory tract and surgical site infections were more frequent ( P < .001)., Conclusions: ID events were less frequent after re-K-Tx. Affected sites differed significantly after f-K-Tx vs re-K-Tx., Competing Interests: Potential conflicts of interest. P. W. S. received travel grants from Pfizer and Gilead, speaker's honorary from Pfizer, and fees for advisory board activity from Pfizer and Gilead outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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25. Anti-GABA A receptor encephalitis 14 months after allogeneic haematopoietic stem-cell transplant for acute myeloid leukaemia.
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Rusche T, Yaldizli Ö, Galbusera R, Mutke M, Halter JP, Lieb J, Matteazzi F, Stelmes A, Bittner J, Grzonka P, Frank N, Cordier D, Hench J, Frank S, Hirsch HH, Fischer U, Kuhle J, Sutter R, Rüegg S, and Fisch U
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- Humans, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute therapy, Graft vs Host Disease
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Competing Interests: Declaration of interests We declare no competing interests relating to the content of the manuscript. ÖY reports honoraria from Biogen. HHH reports grants from Moderna to the University of Basel; and he reports personal consulting fees from AlCuris, Allovir, Moderna, VeraTX, and Roche, and personal honoraria from VeraTX, Takeda, Biotest, and Gilead. UFischer reports research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, Medtronic, Stryker, Penumbra, Rapid medical, Phenox, and Boehringer Ingelheim; consulting fees from Medtronic, Stryker, CSL Behring (fees paid to institution); has membership in a data safety monitoring board for the TITAN trial, IN EXTREMIS trial, LATE-MT trial, Rapid Puls Trial; has membership in the Clinical Event Committee of the COATING Trial (Phenox) and membership in the advisory board for CLS Behring, Acthera, Alexion/Portola, Boehringer Ingelheim (all fees paid to institution); is president of the Swiss Neurological Society.
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- 2024
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26. Impact of bronchoalveolar lavage on the management of immunocompromised hosts.
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Jahn K, Karakioulaki M, Schumann DM, Hirsch HH, Leuzinger K, Grize L, Aliberti S, Sotgiu G, Tamm M, and Stolz D
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- Humans, Bronchoalveolar Lavage Fluid, Bronchoalveolar Lavage methods, Immunocompromised Host, Bronchoscopy methods, Retrospective Studies, Respiratory Tract Infections diagnosis
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Background: Respiratory infections are an important cause of morbidity and mortality in immunocompromised individuals. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is an important tool to detect infectious agents in immunocompromised patients with low respiratory tract infections (LRTI)., Research Question: BAL changes the management of immunocompromised patients with suspected LRTI., Study Design and Methods: Immunocompromised patients with a suspicion of LRTI underwent diagnostic BAL. The primary composite outcome consisted of pre-defined modifications in the management of the immunocompromised patients following BAL. We quantified the impact of bronchoscopy up to 30 days after the procedure., Results: A total of 2666 visits from 1301 patients were included in the study and immunosuppression was classified as haematological (n = 1040; 544 patients), solid organ transplantation (n = 666; 107 patients) and other causes (n = 960; 650 patients). BAL led to a change in management in 52.36% (n = 1396) of all cases. This percentage, as well as the 30-day mortality differed significantly amongst the three groups. Age, C-reactive protein and aetiology of infection determined significantly the risk of 30-day mortality in all patients. In 1.89% (n = 50) of all cases, a combination of 2 respiratory viral agents was identified and 24.23% (n = 646) were diagnosed with a single respiratory viral agent., Interpretation: BAL leads to changes in management in the majority of immunosuppressed patients. There is a high prevalence of multimicrobial infections and respiratory viral infections in immunocompromised patients with respiratory symptoms. Individual virus infection is associated with diverse risk of a negative outcome., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)
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- 2024
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27. Differential Gene Expression of SARS-CoV-2 Positive Bronchoalveolar Lavages: A Case Series.
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Haslbauer JD, Savic Prince S, Stalder AK, Matter MS, Zinner CP, Jahn K, Obermann E, Hanke J, Leuzinger K, Hirsch HH, and Tzankov A
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- Humans, SARS-CoV-2, RNA, Viral, Bronchoalveolar Lavage, Transcriptome, COVID-19 genetics, Asthma
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Background: Transcriptomic data on bronchoalveolar lavage (BAL) from COVID-19 patients are currently scarce., Objectives: This case series seeks to characterize the intra-alveolar immunopathology of COVID-19., Method: BALs were performed on 14 patients (5 COVID-19, of which 3 mild and 2 largely asymptomatic, 9 controls). Controls included asthma (n = 1), unremarkable BALs (n = 3), infections with respiratory syncytial virus (n = 1), influenza B (n = 1), and infections with other coronaviruses (n = 3). SARS-CoV-2 RNA load was measured by quantitative nucleic acid testing, while the detection of other pathogens was performed by immunofluorescence or multiplex NAT., Results: Gene expression profiling showed 71 significantly downregulated and 5 upregulated transcripts in SARS-CoV-2-positive lavages versus controls. Downregulated transcripts included genes involved in macrophage development, polarization, and crosstalk (LGALS3, MARCO, ERG2, BTK, RAC1, CD83), and genes involved in chemokine signaling and immunometabolism (NUPR1, CEBPB, CEBPA, PECAM1, CCL18, PPARG, ALOX5, ALOX5AP). Upregulated transcripts featured genes involved in NK-T cell signaling (GZMA, GZMH, GNLY, PRF1, CD3G). Patients with mild COVID-19 showed a significant upregulation of genes involved in blood mononuclear cell/leukocyte function (G0S2, ANXA6, FCGR2B, ADORA3), coagulation (von Willebrand factor [VWF]), interferon response (IFRD1, IL12RB2), and a zinc metalloprotease elevated in asthma (CPA3) compared to asymptomatic cases. In-silico comparison of the 5 COVID-19 BAL cases to a published cohort of lethal COVID-19 showed a significant upregulation of "antigen processing and presentation" and "lysosome" pathways in lethal cases., Conclusions: These data underscore the heterogeneity of immune response in COVID-19. Further studies with a larger dataset are required to gain a better understanding of the hallmarks of SARS-CoV-2 immunological response., (© 2023 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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28. Consensus position statement on advancing the standardised reporting of infection events in immunocompromised patients.
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Teh BW, Mikulska M, Averbuch D, de la Camara R, Hirsch HH, Akova M, Ostrosky-Zeichner L, Baddley JW, Tan BH, Mularoni A, Subramanian AK, La Hoz RM, Marinelli T, Boan P, Aguado JM, Grossi PA, Maertens J, Mueller NJ, and Slavin MA
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- Humans, Consensus, Immunocompromised Host, Hematopoietic Stem Cell Transplantation
- Abstract
Patients can be immunocompromised from a diverse range of disease and treatment factors, including malignancies, autoimmune disorders and their treatments, and organ and stem-cell transplantation. Infections are a leading cause of morbidity and mortality in immunocompromised patients, and the disease treatment landscape is continually evolving. Despite being a critical but preventable and curable adverse event, the reporting of infection events in randomised trials lacks sufficient detail while inconsistency of categorisation and definition of infections in observational and registry studies limits comparability and future pooling of data. A core reporting dataset consisting of category, site, severity, organism, and endpoints was developed as a minimum standard for reporting of infection events in immunocompromised patients across study types. Further additional information is recommended depending on study type. The standardised reporting of infectious events and attributable complications in immunocompromised patients will improve diagnostic, treatment, and prevention approaches and facilitate future research in this patient group., Competing Interests: Declaration of interests BWT has received grants from Seqirus and MSD, and has been on the advisory board for Takeda, CSL-Behring, and Moderna. RdlC has consulted for Moderna and AstraZeneca, and received honoraria from MSD, Shionogi, Astellas, Moderna, Atara, Pfizer, and Gilead. HHH has consulted for Molecular Partners, Roche, and Vero Tx, and received honoraria from Gilead, MSD, and Vero Tx. LO-Z has received grants from Scynexis, Pulmocide, Gilead, Astellas, Pfizer, T2, and the National Institutes of Health, and has consulted for F2G, GSK, Melinta, Pfizer, Viracor, Cidara, and Gilead. BHT is on the advisory board for Pfizer and MSD. RMLH is on the advisory board for Takeda. PAG has consulted for MSD, Allovir, and Takeda; received honoraria from MSD, Atara, Takeda, and Gilead; and is on the data safety and monitoring and advisory boards for Reithera. NJM has received a grant from the Swiss National Science Foundation and meeting support from Bio Test and Pfizer. MAS has received grants from Gilead, MSD, and F2G. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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29. Urine CXCL10 to Assess BK Polyomavirus Replication After Kidney Transplantation.
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Haller J, Diebold M, Leuzinger K, Wehmeier C, Handschin J, Amico P, Hirt-Minkowski P, Steiger J, Dickenmann M, Hirsch HH, and Schaub S
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- Humans, Biomarkers, Chemokine CXCL10 urine, Urine, BK Virus, Kidney Diseases, Kidney Transplantation adverse effects, Polyomavirus Infections diagnosis, Tumor Virus Infections diagnosis
- Abstract
Background: Urine CXCL10 is a biomarker for renal allograft inflammation induced by rejection, urinary tract infection, or BK polyomavirus (BKPyV) replication. This study aimed to compare urine CXCL10 levels in different stages of BKPyV reactivation and to investigate urine CXCL10 as a biomarker for BKPyV replication., Methods: We included 763 urine samples (235 patients) from an interventional, randomized trial obtained in the context of regular screening for urine CXCL10 levels. All urine samples had a complete urine sediment analysis, no rejection episode noted within 30 d before urine collection, and a urine decoy cell analysis was conducted within ±3 d., Results: Urine CXCL10 levels were 2.31 ng/mmol in samples without BKPyV viruria, slightly rose to 4.35 ng/mmol with BKPyV viruria, and then markedly increased to 16.42 ng/mmol when decoy cells were detectable, but still in the absence of BKPyV DNAemia ( P < 0.001). The highest urine CXCL10 values were observed in samples with BKPyV DNAemia (median 42.59 ng/mmol). The area under the curve of urine CXCL10 levels to detect ≥3 decoy cells was 0.816. At a CXCL10 cutoff of 3 ng/mmol, the negative predictive value was 97%. The area under the curve of urine CXCL10 levels to detect BKPyV DNAemia was 0.882, with a negative predictive value of 99% at a CXCL10 cutoff of 3 ng/mmol., Conclusions: Urine CXCL10 levels are already significantly elevated in BKPyV viruria (especially with decoy cell shedding) and further increase with BKPyV DNAemia. Low urine CXCL10 values can rule out the presence of ≥3 decoy cells and BKPyV DNAemia with high certainty., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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30. American Society of Transplantation and Cellular Therapy Series: #7 - Management of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients.
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Chaer FE, Kaul DR, Englund JA, Boeckh M, Batista MV, Seo SK, Carpenter PA, Navarro D, Hirsch HH, Ison MG, Papanicolaou GA, and Chemaly RF
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- Child, Humans, Transplant Recipients, United States, Communicable Diseases, Hematopoietic Stem Cell Transplantation adverse effects, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus Infections therapy, Respiratory Syncytial Virus, Human
- Abstract
The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transplant Infectious Disease Special Interest Group (TID-SIG) to update the 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was adopted to better serve clinical providers by publishing each standalone topic in the infectious disease series in a concise format of frequently asked questions (FAQ), tables, and figures. Experts in HCT and infectious diseases identified FAQs and then provided answers based on the strength of the recommendation and the level of supporting evidence. In the seventh guideline in the series, we focus on the respiratory syncytial virus (RSV) with FAQs addressing epidemiology, clinical diagnosis, prophylaxis, and treatment. Special consideration was given to RSV in pediatric, cord blood, haploidentical, and T cell-depleted HCT and chimeric antigen receptor T cell therapy recipients, as well as to identify future research directions., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. All rights reserved.)
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- 2023
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31. Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.
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Zeeb M, Tepekule B, Kusejko K, Reiber C, Kälin M, Bartl L, Notter J, Furrer H, Hoffmann M, Hirsch HH, Calmy A, Cavassini M, Labhardt ND, Bernasconi E, Braun DL, Günthard HF, Kouyos RD, and Nemeth J
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- Humans, Switzerland epidemiology, Cohort Studies, HIV Infections complications, HIV Infections epidemiology, Tuberculosis epidemiology, Tuberculosis drug therapy, HIV-1, Latent Tuberculosis epidemiology
- Abstract
Background: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear., Methods: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures., Results: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease., Conclusions: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need., Competing Interests: Potential conflicts of interest . A. C. received grants from Merck Sharp & Dohme (MSD), ViiV Healthcare, and Gilead Sciences for unrelated research. R. D. K. received grants from Gilead Sciences and National Institutes of Health (NIH) for unrelated research. D. L. B. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Pfizer, and AstraZeneca. D. L. B. received honoraria for presentations from Gilead Sciences and Merck. E. B. received grants from MSD for unrelated research. E. B. received payments for travel reimbursement from ViiV, MSD, Gilead Sciences, Pfizer, and Abbvie. E. B. received honoraria for working on the advisory board of ViiV, MSD, Pfizer, Gilead Sciences, AstraZeneca, and Ely Lilly. H. H. H. received honoraria for working on the advisory board of AiCuris, Merck, Vera Dx, and Molecular Partners. H. H. H. received honoraria for presentations from Merck, Gilead Sciences, Biotest, and Vera Dx. J. N. received honoraria for presentations from Oxford Immunotec and ViiV. H. F. G. received honoraria for working on the advisory board of Gilead Sciences, Merck, ViiV, Janssen, Johnson and Johnson, Novartis, and GlaxoSmithKline (GSK). H. F. G. received payments for travel reimbursements from Gilead Sciences. H. F. G. received grants from NIH, Yvonne Jacob Foundation, and Gilead Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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32. Amplicon size and non-encapsidated DNA fragments define plasma cytomegalovirus DNA loads by automated nucleic acid testing platforms: A marker of viral cytopathology?
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Leuzinger K and Hirsch HH
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- Humans, DNA, Viral genetics, Viral Load methods, Deoxyribonucleases, Cytodiagnosis, Cytomegalovirus genetics, Cytomegalovirus Infections diagnosis
- Abstract
Management of cytomegalovirus (CMV) in transplant patients relies on measuring plasma CMV-loads using quantitative nucleic acid testing (QNAT). We prospectively compared the automated Roche-cobas®6800-CMV and Roche-CAP/CTM-CMV with laboratory-developed Basel-CMV-UL54-95bp, and Basel-CMV-UL111a-77bp. Roche-cobas®6800-CMV and Roche-CAP/CTM-CMV were qualitatively concordant in 142/150 cases (95%). In-depth comparison revealed higher CMV-loads of the laboratory-developed assay and correlated with smaller amplicon size. After calibration to the 1.WHO-approved CMV international standard, differences were reduced but remained significant. DNase-I pretreatment significantly reduced CMV-loads for both automated Roche-CAP/CTM-CMV and Roche-cobas®6800-CMV assays, whereby 90% and 95% of samples became undetectable. DNase-I pretreatment also reduced CMV-loads quantified by Basel-CMV-UL54-95bp and Basel-CMV-UL111a-77bp, but remaining detectable in 20% and 35%, respectively. Differences were largest for 110 samples with low-level CMV-DNAemia being detectable but not-quantifiable by Roche-cobas®6800-CMV, whereby the smaller amplicon sizes yielded higher viral loads for concordant positives. We conclude that non-encapsidated fragmented CMV-DNA is the major form of plasma CMV-loads also measured by fully-automated platforms. Amplicons of <150 bp and calibrators are needed for reliable and commutable QNAT-results. We hypothesize that non-encapsidated fragmented CMV-DNA results from lysis of CMV-replicating cells and represent a direct marker of viral cell damage, which contribute to delayed viral load responses despite effective antivirals., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)
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- 2023
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33. Update of recommendations for the management of COVID-19 in patients with haematological malignancies, haematopoietic cell transplantation and CAR T therapy, from the 2022 European Conference on Infections in Leukaemia (ECIL 9).
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Cesaro S, Mikulska M, Hirsch HH, Styczynski J, Meylan S, Cordonnier C, Navarro D, von Lilienfeld-Toal M, Mehra V, Marchesi F, Besson C, Masculano RC, Beutel G, Einsele H, Maertens J, de la Camara R, Ljungman P, and Pagano L
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- Humans, Receptors, Chimeric Antigen, COVID-19, Leukemia complications, Leukemia therapy, Hematologic Neoplasms complications, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects
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- 2023
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34. The Swiss Pathogen Surveillance Platform - towards a nation-wide One Health data exchange platform for bacterial, viral and fungal genomics and associated metadata.
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Neves A, Walther D, Martin-Campos T, Barbie V, Bertelli C, Blanc D, Bouchet G, Erard F, Greub G, Hirsch HH, Huber M, Kaiser L, Leib SL, Leuzinger K, Lazarevic V, Mäusezahl M, Molina J, Neher RA, Perreten V, Ramette A, Roloff T, Schrenzel J, Seth-Smith HMB, Stephan R, Terumalai D, Wegner F, and Egli A
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- Humans, Switzerland epidemiology, Metadata, Genomics methods, Genome, Bacterial, One Health
- Abstract
The Swiss Pathogen Surveillance Platform (SPSP) is a shared secure surveillance platform between human and veterinary medicine, to also include environmental and foodborne isolates. It enables rapid and detailed transmission monitoring and outbreak surveillance of pathogens using whole genome sequencing data and associated metadata. It features controlled data access, complex dynamic queries, dedicated dashboards and automated data sharing with international repositories, providing actionable results for public health and the vision to improve societal well-being and health.
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- 2023
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35. A systematic outbreak investigation of SARS-CoV-2 transmission clusters in a tertiary academic care center.
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von Rotz M, Kuehl R, Durovic A, Zingg S, Apitz A, Wegner F, Seth-Smith HMB, Roloff T, Leuzinger K, Hirsch HH, Kuster S, Battegay M, Mariani L, Schaeren S, Bassetti S, Banderet-Uglioni F, Egli A, and Tschudin-Sutter S
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- Humans, SARS-CoV-2 genetics, Phylogeny, Disease Outbreaks, Tertiary Care Centers, COVID-19 epidemiology, Cross Infection epidemiology
- Abstract
Background: We sought to decipher transmission pathways in healthcare-associated infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within our hospital by epidemiological work-up and complementary whole genome sequencing (WGS). We report the findings of the four largest epidemiologic clusters of SARS-CoV-2 transmission occurring during the second wave of the pandemic from 11/2020 to 12/2020., Methods: At the University Hospital Basel, Switzerland, systematic outbreak investigation is initiated at detection of any nosocomial case of SARS-CoV-2 infection, as confirmed by polymerase chain reaction, occurring more than five days after admission. Clusters of nosocomial infections, defined as the detection of at least two positive patients and/or healthcare workers (HCWs) within one week with an epidemiological link, were further investigated by WGS on respective strains., Results: The four epidemiologic clusters included 40 patients and 60 HCWs. Sequencing data was available for 70% of all involved cases (28 patients and 42 HCWs), confirmed epidemiologically suspected in house transmission in 33 cases (47.1% of sequenced cases) and excluded transmission in the remaining 37 cases (52.9%). Among cases with identical strains, epidemiologic work-up suggested transmission mainly through a ward-based exposure (24/33, 72.7%), more commonly affecting HCWs (16/24, 66.7%) than patients (8/24, 33.3%), followed by transmission between patients (6/33, 18.2%), and among HCWs and patients (3/33, 9.1%, respectively two HCWs and one patient)., Conclusions: Phylogenetic analyses revealed important insights into transmission pathways supporting less than 50% of epidemiologically suspected SARS-CoV-2 transmissions. The remainder of cases most likely reflect community-acquired infection randomly detected by outbreak investigation. Notably, most transmissions occurred between HCWs, possibly indicating lower perception of the risk of infection during contacts among HCWs., (© 2023. The Author(s).)
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- 2023
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36. Molecular Characterization of BK Polyomavirus Replication in Allogeneic Hematopoietic Cell Transplantation Patients.
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Leuzinger K, Kaur A, Wilhelm M, Frank K, Hillenbrand CA, Weissbach FH, and Hirsch HH
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- Humans, CD8-Positive T-Lymphocytes, Antibodies, Neutralizing, BK Virus genetics, Polyomavirus Infections, Hematopoietic Stem Cell Transplantation
- Abstract
Background: High-level BK polyomavirus (BKPyV) replication in allogeneic hematopoietic cell transplantation (HCT) predicts failing immune control and BKPyV-associated hemorrhagic cystitis., Methods: To identify molecular markers of BKPyV replication and disease, we scrutinized BKPyV DNA-loads in longitudinal urine and plasma pairs from 20 HCT patients using quantitative nucleic acid testing (QNAT), DNase-I treatment prior to QNAT, next-generation sequencing (NGS), and tested cell-mediated immunity., Results: We found that larger QNAT amplicons led to under-quantification and false-negatives results (P < .001). DNase-I reduced urine and plasma BKPyV-loads by >90% (P < .001), indicating non-encapsidated BKPyV genomes. DNase-resistant urine BKPyV-loads remained infectious in cell culture. BKPyV genome fragmentation of ≤250 bp impaired NGS coverage of genetic variation using 1000-bp and 5000-bp amplicons. Conversely, 250-bp amplicons captured viral minority variants. We identified genotype-specific and genotype-independent changes in capsid Vp1 or T-antigen predicted to escape from antibody neutralization or cytotoxic CD8 T-cells, respectively. Genotype-specific changes in immunodominant 9mers were associated with reduced or absent CD8 T-cell responses. Thus, failure to control BKPyV replication in HCT Patients may involve insufficient genotype-specific cytotoxic CD8 T-cell responses, potentially predictable by low neutralizing antibodies as well as genotype-independent immune escape., Conclusions: Our results provide new insights for patient evaluation and for designing immune protection through neutralizing antibodies, adoptive T-cell therapy, or vaccines., Competing Interests: Potential conflicts of interest. H. H. H. has received speaker honorarium from Gilead, Biotest, and Vera Therapeutics; and served as consultant for Roche, Molecular Partners, Vera Therapeutics, and AiCuris. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed, (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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37. Vaccine-Preventable Infections Among Solid Organ Transplant Recipients in Switzerland.
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Walti LN, Mugglin C, Mombelli M, Manuel O, Hirsch HH, Khanna N, Mueller NJ, Berger C, Boggian K, Garzoni C, Neofytos D, van Delden C, Mäusezahl M, and Hirzel C
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- Aged, Female, Humans, Male, Middle Aged, Cohort Studies, Switzerland epidemiology, Adult, Communicable Diseases epidemiology, Influenza, Human, Organ Transplantation, Vaccines, Varicella Zoster Virus Infection etiology
- Abstract
Importance: Vaccine responses are decreased in solid organ transplant (SOT) recipients, and given the complexity of implementation, vaccination programs may be suboptimal. The actual burden of vaccine-preventable infections (VPIs) among SOT recipients remains unclear., Objectives: To assess the incidence rate of VPIs among SOT recipients and to evaluate whether SOT recipients are at increased risk for specific VPIs compared with the general population., Design, Setting, and Participants: This nationwide cohort study used data from the Swiss Transplant Cohort Study on VPIs in individuals who underwent SOT from May 2008 to June 2019 (follow-up until December 2019) and data from the Swiss Federal Office of Public Health on notifiable VPIs in the general population in the same period. Data were analyzed from January 2021 to June 2022., Exposures: Solid organ transplant., Main Outcomes and Measures: The main outcomes were the incidence rate of the following VPIs in SOT recipients: hepatitis A and B, diphtheria, Haemophilus influenzae infection, influenza, measles, mumps, pertussis, pneumococcal disease, poliomyelitis, meningococcal disease, rubella, tetanus, tick-borne encephalitis, and varicella zoster virus infection. Age-adjusted standardized incidence ratios were used to assess whether VPIs occurred more frequently in SOT recipients compared with the general population. For SOT recipients, factors associated with occurrence of VPIs were explored and the associated morbidity and mortality assessed., Results: Of 4967 SOT recipients enrolled (median age, 54 years [IQR, 42-62 years]; 3191 [64.2%] male), 593 (11.9%) experienced at least 1 VPI. The overall VPI incidence rate was higher in the population that underwent SOT (30.57 per 1000 person-years [PY]; 95% CI, 28.24-33.10 per 1000 PY) compared with the general population (0.71 per 1000 PY). The standardized age-adjusted incidence ratio for notifiable VPIs in SOT recipients was higher compared with the general population (27.84; 95% CI, 25.00-31.00). In SOT recipients, influenza and varicella zoster virus infection accounted for most VPI episodes (16.55 per 1000 PY [95% CI, 14.85-18.46 per 1000 PY] and 12.83 per 1000 PY [95% CI, 11.40-14.44 per 1000 PY], respectively). A total of 198 of 575 VPI episodes in the population that underwent SOT (34.4%) led to hospital admission, and the occurrence of a VPI was associated with an increased risk for death and/or graft loss (hazard ratio, 2.44; 95% CI, 1.50-3.99; P = .002). In multivariable analysis, age 65 years or older at the time of transplant (incidence rate ratio [IRR], 1.29; 95% CI, 1.02-1.62) and receipt of a lung (IRR, 1.77; 95% CI, 1.38-2.26) or a heart (IRR, 1.40; 95% CI, 1.05-1.88) transplant were associated with an increased risk of VPI occurrence., Conclusions and Relevance: In this study, 11.9% of SOT recipients experienced VPIs, and the incidence rate was higher than in the general population. There was significant morbidity and mortality associated with these infections in the population that underwent SOT, which highlights the need for optimizing immunization strategies.
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- 2023
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38. Frequency matters: comparison of drug resistance mutation detection by Sanger and next-generation sequencing in HIV-1.
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Balakrishna S, Loosli T, Zaheri M, Frischknecht P, Huber M, Kusejko K, Yerly S, Leuzinger K, Perreau M, Ramette A, Wymant C, Fraser C, Kellam P, Gall A, Hirsch HH, Stoeckle M, Rauch A, Cavassini M, Bernasconi E, Notter J, Calmy A, Günthard HF, Metzner KJ, and Kouyos RD
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- Male, Humans, Cohort Studies, Drug Resistance, Viral genetics, Viral Load, Mutation, High-Throughput Nucleotide Sequencing methods, Genotype, HIV-1, HIV Infections drug therapy, HIV Seropositivity drug therapy, Anti-HIV Agents therapeutic use
- Abstract
Background: Next-generation sequencing (NGS) is gradually replacing Sanger sequencing (SS) as the primary method for HIV genotypic resistance testing. However, there are limited systematic data on comparability of these methods in a clinical setting for the presence of low-abundance drug resistance mutations (DRMs) and their dependency on the variant-calling thresholds., Methods: To compare the HIV-DRMs detected by SS and NGS, we included participants enrolled in the Swiss HIV Cohort Study (SHCS) with SS and NGS sequences available with sample collection dates ≤7 days apart. We tested for the presence of HIV-DRMs and compared the agreement between SS and NGS at different variant-calling thresholds., Results: We included 594 pairs of SS and NGS from 527 SHCS participants. Males accounted for 80.5% of the participants, 76.3% were ART naive at sample collection and 78.1% of the sequences were subtype B. Overall, we observed a good agreement (Cohen's kappa >0.80) for HIV-DRMs for variant-calling thresholds ≥5%. We observed an increase in low-abundance HIV-DRMs detected at lower thresholds [28/417 (6.7%) at 10%-25% to 293/812 (36.1%) at 1%-2% threshold]. However, such low-abundance HIV-DRMs were overrepresented in ART-naive participants and were in most cases not detected in previously sampled sequences suggesting high sequencing error for thresholds <3%., Conclusions: We found high concordance between SS and NGS but also a substantial number of low-abundance HIV-DRMs detected only by NGS at lower variant-calling thresholds. Our findings suggest that a substantial fraction of the low-abundance HIV-DRMs detected at thresholds <3% may represent sequencing errors and hence should not be overinterpreted in clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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39. AGIHO guideline on evidence-based management of COVID-19 in cancer patients: 2022 update on vaccination, pharmacological prophylaxis and therapy in light of the omicron variants.
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Giesen N, Busch E, Schalk E, Beutel G, Rüthrich MM, Hentrich M, Hertenstein B, Hirsch HH, Karthaus M, Khodamoradi Y, Koehler P, Krüger W, Koldehoff M, Krause R, Mellinghoff SC, Penack O, Sandherr M, Seggewiss-Bernhardt R, Spiekermann K, Sprute R, Stemler J, Weissinger F, Wörmann B, Wolf HH, Cornely OA, Rieger CT, and von Lilienfeld-Toal M
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- Humans, SARS-CoV-2, Vaccination, COVID-19 prevention & control, COVID-19 complications, Neoplasms therapy, Neoplasms drug therapy, Communicable Diseases complications, Communicable Diseases drug therapy
- Abstract
The novel coronavirus SARS-CoV-2 and the associated infectious disease COVID-19 pose a significant challenge to healthcare systems worldwide. Patients with cancer have been identified as a high-risk population for severe infections, rendering prophylaxis and treatment strategies for these patients particularly important. Rapidly evolving clinical research, resulting in the recent advent of various vaccines and therapeutic agents against COVID-19, offers new options to improve care and protection of cancer patients. However, ongoing epidemiological changes and rise of new virus variants require repeated revisions and adaptations of prophylaxis and treatment strategies to meet these new challenges. Therefore, this guideline provides an update on evidence-based recommendations with regard to vaccination, pharmacological prophylaxis and treatment of COVID-19 in cancer patients in light of the currently dominant omicron variants. It was developed by an expert panel of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) based on a critical review of the most recent available data., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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40. Quantifying and Predicting Ongoing Human Immunodeficiency Virus Type 1 Transmission Dynamics in Switzerland Using a Distance-Based Clustering Approach.
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Labarile M, Loosli T, Zeeb M, Kusejko K, Huber M, Hirsch HH, Perreau M, Ramette A, Yerly S, Cavassini M, Battegay M, Rauch A, Calmy A, Notter J, Bernasconi E, Fux C, Günthard HF, Pasin C, and Kouyos RD
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- Humans, Switzerland epidemiology, Cohort Studies, Prospective Studies, Phylogeny, Cluster Analysis, HIV-1 genetics, HIV Infections
- Abstract
Background: Despite effective prevention approaches, ongoing human immunodeficiency virus 1 (HIV-1) transmission remains a public health concern indicating a need for identifying its drivers., Methods: We combined a network-based clustering method using evolutionary distances between viral sequences with statistical learning approaches to investigate the dynamics of HIV transmission in the Swiss HIV Cohort Study and to predict the drivers of ongoing transmission., Results: We found that only a minority of clusters and patients acquired links to new infections between 2007 and 2020. While the growth of clusters and the probability of individual patients acquiring new links in the transmission network was associated with epidemiological, behavioral, and virological predictors, the strength of these associations decreased substantially when adjusting for network characteristics. Thus, these network characteristics can capture major heterogeneities beyond classical epidemiological parameters. When modeling the probability of a newly diagnosed patient being linked with future infections, we found that the best predictive performance (median area under the curve receiver operating characteristic AUCROC = 0.77) was achieved by models including characteristics of the network as predictors and that models excluding them performed substantially worse (median AUCROC = 0.54)., Conclusions: These results highlight the utility of molecular epidemiology-based network approaches for analyzing and predicting ongoing HIV transmission dynamics. This approach may serve for real-time prospective assessment of HIV transmission., Competing Interests: Potential conflicts of interest . R. D. K. has received grants from the Swiss National Science Foundation (for this work) and Gilead Sciences (outside the submitted work). H.F.G has received unrestricted research grants from the Swiss National Science Foundation, NIH, Yvonne Jacob Foundation and Gilead Sciences; fees for data and safety monitoring board, consultancy or advisory board membership from Merck, Gilead, ViiV, Johnson and Johnson, Janssen, and Novartis. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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41. Impact of nucleic acid extraction procedures on human papillomavirus (HPV) detection and genotyping.
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Naegele K, Weissbach FH, Leuzinger K, Gosert R, Bubendorf L, and Hirsch HH
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- Female, Humans, Human Papillomavirus Viruses, Genotype, Papillomaviridae genetics, DNA, Viral genetics, Papillomavirus Infections, Uterine Cervical Neoplasms, Precancerous Conditions, Carcinoma, Squamous Cell
- Abstract
Human papillomavirus (HPV) infections are often asymptomatic, but some of the >200 HPV genotypes confer a high risk for precancerous cervical lesions and cervical cancer. Current clinical management of HPV infections relies on reliable nucleic acid testing detection and genotyping. We prospectively compared nucleic acid extraction without and with prior centrifugation enrichment for detecting and genotyping HPV in cervical swabs with atypical squamous or glandular cells. Consecutive swabs were analyzed from 45 patients with atypical squamous or glandular cells. Nucleic acids were extracted in parallel using three procedures, Abbott-M2000, Roche-MagNA-Pure-96 Large-Volume Kit without (Roche-MP-large) and with prior centrifugation (Roche-MP-large/spin) and tested using Seegene-Anyplex-II HPV28. In total, 54 HPV-genotypes were detected in 45 samples, 51 by Roche-MP-large/spin, 48 by Abbott-M2000 and 42 by Roche-MP-large. The overall concordance was 80% for detecting any HPV and 74% for specific HPV-genotypes. Roche-MP-large/spin and Abbott-M2000 showed the highest concordance for HPV detection (88.9%; kappa 0.78), and genotyping (88.5%). Two and more HPV-genotypes were detected in 15 samples, often with one HPV being more abundant. Dilution series confirmed the specific detection of multiple HPV-genotypes and their relative abundance. In 285 consecutive follow-up samples extracted by Roche-MP-large/spin, the top three detected genotypes were the high-risk HPV16, HPV53, HPV56 and the low-risk HPV42, HPV54 and HPV61. Rate and breadth of HPV detection in cervical swabs depends on extraction protocols being highest after centrifugation/enrichment. As multivalent HPV-vaccine coverage increases, detecting the evolving HPV virome depends on improved extraction and broader genotype coverage., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)
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- 2023
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42. Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data.
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Nadeau SA, Vaughan TG, Beckmann C, Topolsky I, Chen C, Hodcroft E, Schär T, Nissen I, Santacroce N, Burcklen E, Ferreira P, Jablonski KP, Posada-Céspedes S, Capece V, Seidel S, Santamaria de Souza N, Martinez-Gomez JM, Cheng P, Bosshard PP, Levesque MP, Kufner V, Schmutz S, Zaheri M, Huber M, Trkola A, Cordey S, Laubscher F, Gonçalves AR, Aeby S, Pillonel T, Jacot D, Bertelli C, Greub G, Leuzinger K, Stange M, Mari A, Roloff T, Seth-Smith H, Hirsch HH, Egli A, Redondo M, Kobel O, Noppen C, du Plessis L, Beerenwinkel N, Neher RA, Beisel C, and Stadler T
- Subjects
- Humans, Public Health, Switzerland epidemiology, Communicable Disease Control, Genome, Viral genetics, Phylogeny, SARS-CoV-2 genetics, COVID-19 genetics
- Abstract
Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Switzerland in 2020-the sixth largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrasted these estimates with simple null models representing the absence of certain public health measures. We show that Switzerland's border closures decoupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86 to 98% reduction in introductions during Switzerland's strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Last, we quantified local transmission dynamics once introductions into Switzerland occurred using a phylodynamic model. We found that transmission slowed 35 to 63% upon outbreak detection in summer 2020 but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.
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- 2023
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43. Cytomegalovirus in the transplant setting: Where are we now and what happens next? A report from the International CMV Symposium 2021.
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Kotton CN, Torre-Cisneros J, Aguado JM, Alain S, Baldanti F, Baumann G, Boeken U, de la Calle M, Carbone J, Ciceri F, Comoli P, Couzi L, Danziger-Isakov L, Fernández-Ruiz M, Girmenia C, Grossi PA, Hirsch HH, Humar A, Kamar N, Kotton C, Ljungman P, Malagola M, Mira E, Mueller N, Sester M, Teng CJ, Torre-Cisneros J, Ussetti P, Westall G, Wolf D, and Zamora M
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- Humans, Cytomegalovirus, Antiviral Agents therapeutic use, Cytomegalovirus Infections diagnosis, Cytomegalovirus Infections epidemiology, Cytomegalovirus Infections prevention & control, Organ Transplantation adverse effects, Lung Transplantation, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
The CMV Symposium in September 2021 was an international conference dedicated to cytomegalovirus (CMV) infection after solid organ or hematopoietic stem cell transplantation. This review provides an overview of the presentations given by the expert faculty, supplemented with educational clinical cases. Topics discussed include CMV epidemiology and diagnosis, the burden of CMV infection and disease, CMV-specific immunity and management of CMV in transplant settings. Major advances in the prevention and treatment of CMV in the past decade and increased understanding of CMV immunity have led to improved patient outcomes. In the future, management algorithms may be individualized based on the transplant recipient's immune profile, which will mark the start of a new era for patients with CMV., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)
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- 2022
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44. BK Polyomavirus Consensus.
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Hirsch HH, Mengel M, and Kamar N
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- Humans, Consensus, BK Virus, Polyomavirus Infections, Kidney Transplantation
- Abstract
Competing Interests: Potential conflicts of interest. M. M. reports a research grant from Alberta Innovates unrelated to this work; consulting fees paid to author from CSL Behring and from Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events paid to author from CSL Behring; and an unpaid role with Banff Foundation for Allograft Pathology. H. H. H. reports honoraria as a consultant for Molecular Probes, Vera Therapeutics, and AiCuris and honoraria as a Biotest speaker, Roche advisory panel member, and Gilead speaker. N. K. reports honoraria paid to author from Biotest (speaker), Astellas, Novartis, MSD, Takeda, and ExeVir. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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- 2022
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45. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study.
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Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Müller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli Ö, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Pröbstel AK, and Hutter G
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- Humans, Cross-Sectional Studies, SARS-CoV-2, Autoimmunity, Prospective Studies, Post-Acute COVID-19 Syndrome, COVID-19
- Abstract
Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection., (© 2022. The Author(s).)
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- 2022
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46. Nitrogen fixation and mucilage production on maize aerial roots is controlled by aerial root development and border cell functions.
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Pankievicz VCS, Delaux PM, Infante V, Hirsch HH, Rajasekar S, Zamora P, Jayaraman D, Calderon CI, Bennett A, and Ané JM
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Exploring natural diversity for biological nitrogen fixation in maize and its progenitors is a promising approach to reducing our dependence on synthetic fertilizer and enhancing the sustainability of our cropping systems. We have shown previously that maize accessions from the Sierra Mixe can support a nitrogen-fixing community in the mucilage produced by their abundant aerial roots and obtain a significant fraction of their nitrogen from the air through these associations. In this study, we demonstrate that mucilage production depends on root cap and border cells sensing water, as observed in underground roots. The diameter of aerial roots correlates with the volume of mucilage produced and the nitrogenase activity supported by each root. Young aerial roots produce more mucilage than older ones, probably due to their root cap's integrity and their ability to produce border cells. Transcriptome analysis on aerial roots at two different growth stages before and after mucilage production confirmed the expression of genes involved in polysaccharide synthesis and degradation. Genes related to nitrogen uptake and assimilation were up-regulated upon water exposure. Altogether, our findings suggest that in addition to the number of nodes with aerial roots reported previously, the diameter of aerial roots and abundance of border cells, polysaccharide synthesis and degradation, and nitrogen uptake are critical factors to ensure efficient nitrogen fixation in maize aerial roots., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pankievicz, Delaux, Infante, Hirsch, Rajasekar, Zamora, Jayaraman, Calderon, Bennett and Ané.)
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- 2022
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47. Characterization of pathogen-inactivated COVID-19 convalescent plasma and responses in transfused patients.
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Weisser M, Khanna N, Hedstueck A, Sutter ST, Roesch S, Stehle G, Sava M, Deigendesch N, Battegay M, Infanti L, Holbro A, Bassetti S, Pargger H, Hirsch HH, Leuzinger K, Kaiser L, Vu DL, Baur K, Massaro N, Busch MP, Simmons G, Stone M, Felgner PL, de Assis RR, Khan S, Tsai CT, Robinson PV, Seftel D, Irsch J, Bagri A, Buser AS, and Corash L
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- Aged, Antibodies, Neutralizing, Antibodies, Viral, Case-Control Studies, Humans, Immunization, Passive, Middle Aged, COVID-19 Serotherapy, COVID-19 therapy, SARS-CoV-2
- Abstract
Background: Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics., Study Design and Methods: In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients., Results: Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients., Discussion: PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays., (© 2022 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)
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- 2022
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48. A Systematic Molecular Epidemiology Screen Reveals Numerous Human Immunodeficiency Virus (HIV) Type 1 Superinfections in the Swiss HIV Cohort Study.
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Chaudron SE, Leemann C, Kusejko K, Nguyen H, Tschumi N, Marzel A, Huber M, Böni J, Perreau M, Klimkait T, Yerly S, Ramette A, Hirsch HH, Rauch A, Calmy A, Vernazza P, Bernasconi E, Cavassini M, Metzner KJ, Kouyos RD, and Günthard HF
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- Cohort Studies, Humans, Molecular Epidemiology, Phylogeny, Switzerland epidemiology, HIV Infections, HIV-1, Superinfection epidemiology, Vaccines
- Abstract
Background: Studying human immunodeficiency virus type 1 (HIV-1) superinfection is important to understand virus transmission, disease progression, and vaccine design. But detection remains challenging, with low sampling frequencies and insufficient longitudinal samples., Methods: Using the Swiss HIV Cohort Study (SHCS), we developed a molecular epidemiology screening for superinfections. A phylogeny built from 22 243 HIV-1 partial polymerase sequences was used to identify potential superinfections among 4575 SHCS participants with longitudinal sequences. A subset of potential superinfections was tested by near-full-length viral genome sequencing (NFVGS) of biobanked plasma samples., Results: Based on phylogenetic and distance criteria, 325 potential HIV-1 superinfections were identified and categorized by their likelihood of being detected as superinfections due to sample misidentification. NFVGS was performed for 128 potential superinfections; of these, 52 were confirmed by NFVGS, 15 were not confirmed, and for 61 sampling did not allow confirming or rejecting superinfection because the sequenced samples did not include the relevant time points causing the superinfection signal in the original screen. Thus, NFVGS could support 52 of 67 adequately sampled potential superinfections., Conclusions: This cohort-based molecular approach identified, to our knowledge, the largest population of confirmed superinfections, showing that, while rare with a prevalence of 1%-7%, superinfections are not negligible events., Competing Interests: Potential conflicts of interest. The institution of E. B. received fees for E. B. participation in advisory boards and travel grants from Gilead Sciences, MSD, ViiV Healthcare, Pfizer, AbbVie, and Sandoz. K. J. M. has received advisory board honoraria from Gilead Sciences; has received travel grants and honoraria from Gilead Sciences, Roche Diagnostics, GlaxoSmithKline, Merck Sharp & Dohme, Bristol-Myers Squibb, ViiV, and Abbott; the University of Zurich received research grants from Gilead Science, Novartis, Roche, and Merck Sharp & Dohme for studies for which K. J. M. serves as principal investigator. H. F. G. has received unrestricted research grants from Gilead Sciences and Roche; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck, and ViiV Healthcare; and grants from SystemsX, and the National Institutes of Health. The institution of H. F. G. received educational grants from Gilead Sciences, ViiV, MSD, AbbVie, and Sandoz. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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49. Infection Risk in the First Year After ABO-incompatible Kidney Transplantation: A Nationwide Prospective Cohort Study.
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Hirzel C, Projer L, Atkinson A, Surial B, Mueller NJ, Manuel O, Mombelli M, van Delden C, Hirsch HH, Boggian K, Walti LN, Sidler D, Hadaya K, Dickenmann M, Müller TF, Binet I, Golshayan D, and Huynh-Do U
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- ABO Blood-Group System, Blood Group Incompatibility, Cohort Studies, Graft Rejection epidemiology, Graft Survival, Humans, Living Donors, Prospective Studies, Anemia, Hemolytic, Autoimmune, Infections epidemiology, Infections etiology, Kidney Transplantation adverse effects, Kidney Transplantation methods
- Abstract
Background: ABO-incompatible (ABOi) kidney transplantation (KT) expands the kidney donor pool and may help to overcome organ shortage. Nonetheless, concerns about infectious complications associated with ABOi-KT have been raised., Methods: In a nationwide cohort (Swiss Transplant Cohort Study), we compared the risk for infectious complications among ABOi and ABO-compatible (ABOc) renal transplant recipients. Infections needed to fulfill rigorous, prespecified criteria to be classified as clinically relevant. Unadjusted and adjusted competing risk regression models were used to compare the time to the first clinically relevant infection among ABOi-KT and ABOc-KT recipients. Inverse probability weighted generalized mixed-effects Poisson regression was used to estimate incidence rate ratios for infection., Results: We included 757 living-donor KT recipients (639 ABOc; 118 ABOi) and identified 717 infection episodes. The spectrum of causative pathogens and the anatomical sites affected by infections were similar between ABOi-KT and ABOc-KT recipients. There was no significant difference in time to first posttransplant infection between ABOi-KT and ABOc-KT recipients (subhazard ratio, 1.24; 95% confidence interval [CI], 0.93-1.66; P = 0.142). At 1 y, the crude infection rate was 1.11 (95% CI, 0.93-1.33) episodes per patient-year for ABOi patients and 0.94 (95% CI, 0.86-1.01) for ABOc-KT recipients. Inverse probability weighted infection rates were similar between groups (adjusted incidence rate ratio, 1.12; 95% CI, 0.83-1.52; P = 0.461)., Conclusions: The burden of infections during the first year posttransplant was high but not relevantly different in ABOi-KT and ABOc-KT recipients. Our results highlight that concerns regarding infectious complications should not affect the implementation of ABOi-KT programs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2022
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50. Impact of SARS-CoV-2 Omicron on Rapid Antigen Testing Developed for Early-Pandemic SARS-CoV-2 Variants.
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Leuzinger K, Roloff T, Egli A, and Hirsch HH
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- Humans, Nucleocapsid Proteins genetics, Pandemics, COVID-19 diagnosis, SARS-CoV-2 genetics
- Abstract
Rapid antigen tests (RATs) are widely used for point-of-care or self-testing to identify SARS-CoV-2 (SCoV2), but currently circulating Omicron variants may impair detection. In this study, we prospectively evaluated the Roche-SARS-CoV-2-Antigen and Acon-FlowFlex-SARS-CoV-2-Antigen in 150 consecutively collected nasopharyngeal patient swabs (50 SCoV2 RNA undetectable; 100 SCoV2 Omicron BA.1). Omicron BA.1 results were compared to 92 Ct-matched early-pandemic SCoV2 variants (B.1.160 and B.1.177), to 100 Omicron BA.2 positive and to 100 Omicron BA.5 positive samples. For Omicron BA.1, Roche-SARS-CoV-2-Antigen detected 87% of samples having Ct-values <29 reflecting 3.6% lower rates compared to B.1.160 and B.1.177. Acon-FlowFlex-SARS-CoV-2-Antigen was less affected and detected 90% of Omicron BA.1 with Ct-values <29. Omicron BA.2 and BA.5 detection rates were significantly reduced by 20% and 10%, respectively, for the Roche-SARS-CoV-2-Antigen in samples with Ct-values <29 but remained similar for Acon-FlowFlex-SARS-CoV-2-Antigen. RATs need to be continuously evaluated as new SCoV2-variants emerge. Spreading of Omicron-BA.2, and the recently emerged Omicron BA.5 variant, may not only result from escape from postvaccine or postinfection immunity, but also from false-negative RATs misguiding point-of-care and self-testing decisions at times of restricted molecular testing. IMPORTANCE Antigen tests are widely used for rapid identification of SCoV2-positive cases and their increased risk of transmission. At present, there are several FDA- and CE-cleared tests available in North America and Europe. However, their diagnostic performance has been evaluated with early-pandemic variants. This study provides evidence that variation within the nucleocapsid protein as seen in recently emerged and now globally spreading Omicron BA.2 and BA.5 variants significantly impairs detection rates of widely used antigen tests. Consequently, antigen tests need to be reevaluated when new pandemic SCoV2 variants emerge and start to predominate globally.
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- 2022
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