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Beyer AP, Moise PA, Wong M, Gao W, Xiang C, Shen P, Pavlakis M, Vincenti F, Wang W. Clinical events and healthcare resource utilization associated with neutropenia and leukopenia among adult kidney transplant recipients receiving valganciclovir. World J Transplant 2025; 15:102671. [DOI: 10.5500/wjt.v15.i2.102671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients, although the impact of these events on healthcare resource utilization (HCRU) and clinical outcomes is unclear.
AIM To quantify clinical events and HCRU associated with neutropenia and leukopenia among adults receiving valganciclovir and/or ganciclovir post-kidney transplantation.
METHODS Adult kidney transplant recipients receiving valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database from 2012 to 2021. Patient characteristics were evaluated in the 1-year period pre-first transplant. HCRU and adjusted event rates per person-year were evaluated in follow-up year 1 and years 2-5 after first kidney transplantation among cohorts with vs without neutropenia and/or leukopenia.
RESULTS Of 15398 identified patients, the average age was 52.39 years and 58.70% were male. Patients with neutropenia and/or leukopenia had greater risk of clinical events for CMV-related events, opportunistic infections, use of granulocyte colony stimulating factor, and hospitalizations (relative risk > 1 in year 1 and years 2-5). Patients with vs without neutropenia and/or leukopenia had higher HCRU in year 1 and years 2-5 post kidney transplantation, including the mean number of inpatient admissions (year 1: 3.47 vs 2.76; years 2-5: 2.70 vs 2.29) and outpatient visits (48.97 vs 34.42; 31.73 vs 15.59, respectively), as well as the mean number of labs (1654.55 vs 1182.27; 622.37 vs 327.89).
CONCLUSION Adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation had greater risk of neutropenia and/or leukopenia, which were associated with higher clinical event rates and HCRU up to 5 years post-transplantation. These findings suggest the need for alternative prophylaxis options with lower myelosuppressive effects to improve patient outcomes.
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Affiliation(s)
- Andrew P Beyer
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Pamela A Moise
- Medical Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Michael Wong
- Scientific Affairs, Merck & Co., Inc., Rahway, NJ 07065, United States
| | - Wei Gao
- Analysis Group, Boston, MA 02199, United States
| | | | | | - Martha Pavlakis
- The Transplant Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
| | - Flavio Vincenti
- The Transplant Services, University of California San Francisco, San Francisco, CA 94143, United States
| | - Weijia Wang
- Department of Value and Implementation Outcomes Research, Merck & Co., Inc., Rahway, NJ 07065, United States
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Kofahi HM, Swedan SF, Aljezawi M. Cytomegalovirus and Epstein-Barr virus infections among Jordanians: seroprevalence and associated factors. BMC Infect Dis 2025; 25:724. [PMID: 40399872 PMCID: PMC12093734 DOI: 10.1186/s12879-025-11110-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Accepted: 05/13/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are widespread infections, with seroprevalence rates varying by region and demographic characteristics. This study aimed to examine the seroprevalence of EBV and CMV in the Jordanian population and explore possible risk factors associated with these infections. METHODS A total of 1,507 individuals were recruited through convenience sampling from hospitals located in the central and northern regions of Jordan. Participants were stratified by age, sex, and geographic area. Blood samples were analyzed for EBV-VCA and CMV IgG antibodies using ELISA. Demographic and socioeconomic information was also collected. To identify potential risk factors, multivariate logistic regression was conducted, focusing on variables such as age, sex, marital status, education level, monthly income, region, and type of residence. RESULTS The overall seroprevalence was 88.7% for CMV-IgG and 91.0% for EBV-IgG. The seroprevalence of both CMV and EBV increased with age from 62.4% and 70.6%, respectively, in children under five years of age to 100.0% and 96.5% in participants aged 60 years and above. Regression analysis indicated that older age and being ever married (i.e., married, divorced, or widowed) were significantly associated with higher seroprevalence of both viruses. Additionally, having a monthly income of 64.3 JD or more per individual was independently linked to higher EBV seroprevalence. CONCLUSION EBV and CMV seroprevalence in Jordan was remarkably high. Age was the most prominent risk factor, with marital status and income contributing as independent predictors. These findings offer a valuable reference point for future public health efforts, including surveillance and vaccination strategies targeting high-risk groups.
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Affiliation(s)
- Hassan M Kofahi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
| | - Samer F Swedan
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan
| | - Maen Aljezawi
- Community and Mental Health Nursing Department, Faculty of Nursing, Al Al Bayt University, P.O. Box 130040, Mafraq, 25113, Jordan
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Hill G, Gao H, Fan Y, Zhang R, Wang L, Zong Z, Zhou Y, Qin D, Hou J. Pharmacokinetics and Safety Study of HN0141, a Novel Anti-Human Cytomegalovirus Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev 2025. [PMID: 40377417 DOI: 10.1002/cpdd.1542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 02/21/2025] [Indexed: 05/18/2025]
Abstract
HN0141 is a human cytomegalovirus (HCMV) DNA terminase complex inhibitor being developed for prophylaxis and/or preemptive treatment of HCMV infection and diseases. This study evaluated the safety, tolerability, and pharmacokinetics (PK) of HN0141, following oral administration in healthy volunteers. The double-blind, placebo-controlled Phase 1 study comprised Part 1, an escalating, single-dose study involving 50-, 100-, 200-, 300-, 400-, and 525-mg doses; and Part 2, a multiple-dose study over 7 days involving 50-, 100-, 200-, and 400-mg twice-daily doses. HN0141 was rapidly absorbed following oral doses, with median time to maximum concentration achieved within 1-2 hours across all doses. At doses ranging from 50 to 100 mg, the PK profile was reasonably linear, while at doses above 200 mg, the PK profile was more than proportional. The predicted therapeutic dose would be 50-200 mg twice daily, which is at a reasonable linear PK range. All exposures tested (up to 525-mg single dose and 400-mg twice-daily multiple doses) were within the no-observed-adverse-effect level defined in animal toxicity studies. There was a mild accumulation on systemic exposure at steady state, which was achieved within 72 hours of multiple twice-daily dosing. No serious or severe adverse events were reported. HN0141's PK profile favors the twice-daily dosing, which gives a smaller concentration variation during the treatment, and thus could bring a better treatment effect with sufficient convenience. These Phase 1 data in safety and PK profile warrant further drug development in both preemptive and prophylactic treatment in patients with HCMV.
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Affiliation(s)
- George Hill
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Hong Gao
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Yingzhe Fan
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Rui Zhang
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Lu Wang
- Phase I Trial Center, PKU Care Luzhong Hospital, Shandong, China
| | - Zhaoshan Zong
- Phase I Trial Center, PKU Care Luzhong Hospital, Shandong, China
| | - Yi Zhou
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Donghui Qin
- Clinical and Medical Science Department, Phaeno Therapeutics Co. Ltd, Hangzhou, China
| | - Jie Hou
- Phase I Trial Center, PKU Care Luzhong Hospital, Shandong, China
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Kawamura S, Nakagawa D, Nagayama T, Katayama Y, Doki N, Takeda W, Nishida T, Matsuoka KI, Ikeda T, Ohigashi H, Sawa M, Fukushima K, Kanda J, Serizawa K, Onizuka M, Fukuda T, Atsuta Y, Kanda Y, Nakasone H. Impacts of donor age and HLA mismatch on HCT outcomes differ according to the donor CMV serostatus in unrelated allo-HCT. Blood Adv 2025; 9:2356-2365. [PMID: 39808797 DOI: 10.1182/bloodadvances.2024014408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/16/2025] Open
Abstract
ABSTRACT In unrelated allogeneic hematopoietic cell transplantation (allo-HCT), older and/or HLA-mismatched donors are known risk factors for survival outcomes. In healthy individuals, cytomegalovirus (CMV) seropositivity is associated with impaired adaptive immune systems. We assessed whether the adverse effects of donor risk factors are influenced by the donor CMV serostatus. We analyzed 5836 patients with CMV seropositivity who received unrelated allo-HCT. We divided the entire cohort into 2 cohorts according to the donor CMV serostatus: CMV positive (DP) and negative (DN). We also stratified each cohort into 4 groups based on donor age (aged ≥40 or <40 years) and HLA parity (8/8 or 7/8): Young88 and Old88, and Young78 and Old78, respectively. In the CMV-DP cohort, the Old88 (hazard ratio [HR], 1.20; P = .012), Young78 (HR, 1.35; P < .001), and Old78 (HR, 1.60; P < .001) groups were associated with inferior overall survival (OS) than the Young88 group. In contrast, in the CMV-DN cohort, neither donor age nor HLA disparity was associated with inferior OS. The adverse impact of donor age was different between the cohorts (CMV-DP: HR, 1.19; P = .001; CMV-DN: HR, 1.04; P = .53; P for interaction, .070), as was the impact of HLA (CMV-DP: HR, 1.34; P < .001; CMV-DN: HR, 1.08; P = .23; P for interaction, .012). The impacts of donor age and HLA mismatch on OS might differ according to the donor CMV serostatus. In unrelated allo-HCT from a CMV-seronegative donor, an HLA-mismatched older donor may be able to be selected without affecting OS.
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Affiliation(s)
- Shunto Kawamura
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Daishi Nakagawa
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takashi Nagayama
- Division of Cell Transplantation and Transfusion, Jichi Medical University, Shimotsuke, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Wataru Takeda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Tetsuya Nishida
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Ken-Ichi Matsuoka
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
| | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Ohigashi
- Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
| | - Masashi Sawa
- Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan
| | - Kentaro Fukushima
- Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan
| | - Junya Kanda
- Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kentaro Serizawa
- Division of Hematology and Rheumatology, Department of Internal Medicine, Kindai University Hospital, Osakasayama, Japan
| | - Makoto Onizuka
- Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
| | - Takahiro Fukuda
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiko Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
- Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Hematology, Jichi Medical University, Shimotsuke, Japan
| | - Hideki Nakasone
- Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
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Quisias J, Gill MJ, Coburn SB, Krentz HB, Beckthold B, Fonseca K, Parkins MD, Lang R. Cytomegalovirus serostatus among people with HIV, characterizing the prevalence, risk factors, and association with immune recovery. HIV Med 2025. [PMID: 40295208 DOI: 10.1111/hiv.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 04/14/2025] [Indexed: 04/30/2025]
Abstract
INTRODUCTION Cytomegalovirus (CMV) infection is common among people with HIV (PWH), and may be associated with negative outcomes. We aimed to identify the seroprevalence of CMV between 01 January 1998 and 01 June 2022 among PWH accessing care at the Southern Alberta Clinic (SAC) and the associated risk factors. We also aimed to assess the impact of CMV seropositivity on CD4+ T-cells and CD4+/CD8+ ratio recovery among PWH who maintain HIV viral suppression. METHODS Poisson regression models with robust variance estimated crude and adjusted prevalence ratios and 95% confidence intervals to identify risk factors for CMV seronegativity. Among PWH maintaining viral suppression, trends in the median CD4+ T-cell count and CD4+/CD8+ ratio were visualized, and continuous time-to-event Cox proportional hazard models estimated hazards ratios (aHR) for CD4+ cell count recovery to ≥500 cells/mm3 and CD4+/CD8+ ratio of >1 at 10 years by CMV serostatus. RESULTS Among 3249 PWH, 2954 (91%) were CMV seropositive. CMV seronegativity was associated with younger ages, male sex, non-Hispanic white race and an education of ≥12 years. While CMV seronegativity did not affect CD4+ T-cell recovery following HIV viral suppression (aHR 1.15 [0.89-1.48]), it was associated with a greater likelihood of CD4+/CD8+ ratio normalization (aHR 2.38 [1.85-3.07]) at 10 years of follow-up. CONCLUSIONS CMV is a common coinfection among PWH. We found that CMV positivity among PWH maintaining HIV viral suppression, while not associated with CD4+ T-cell recovery, was associated with a reduced CD4+/CD8+ ratio recovery. This suggests an association with chronic CMV infection-mediated immune activation and inflammation among PWH.
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Affiliation(s)
- Joshua Quisias
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - M John Gill
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Sally B Coburn
- Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hartmut B Krentz
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
| | - Brenda Beckthold
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
| | - Kevin Fonseca
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
- Alberta Public Health Laboratory, Alberta Health Services, Calgary, Alberta, Canada
| | - Michael D Parkins
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Raynell Lang
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Southern Alberta Clinic, Alberta Health Services, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
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Boquett JA, Sauter J, Schmidt AH, Maiers M, Hollenbach JA. Human leukocyte antigen variation is associated with cytomegalovirus serostatus in healthy individuals. Am J Hum Genet 2025; 112:913-926. [PMID: 40049169 DOI: 10.1016/j.ajhg.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 03/12/2025] Open
Abstract
Cytomegalovirus (CMV) is a common β-herpes virus worldwide with an estimated seroprevalence among the general population of 83%. Primary infection is usually benign; however, CMV can cause severe morbidity in newborns in whom it is acquired congenitally, as well as immunocompromised individuals. Understanding the role of immunogenetic variation in risk for CMV infection can provide insight into the immune control of this ubiquitous pathogen. Here, we evaluated the association of human leukocyte antigen (HLA) genetic variation with CMV seropositivity in more than 518,000 individuals from two independent cohorts. We found three HLA class II alleles (HLA-DRB1∗04:03 with risk; HLA-DRB1∗01:03 and HLA-DRB1∗07:01 with protection) to be significantly associated with CMV serostatus across both cohorts and in multiple population subgroups. Interestingly, HLA-DRB1∗04:03 and HLA-DRB1∗01:03, the alleles with the strongest observed effect, are relatively rare, while common homologous alleles show no association with CMV. We show that these differences are mediated by changes in charge and volume to two key pockets in the peptide-binding groove of the HLA molecule, providing a structural basis for the observed association. Our results provide population-scale evidence for the role of HLA in mediating infection with this ubiquitous human virus and a framework for understanding immunological conditions necessary for efficient viral control.
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Affiliation(s)
- Juliano A Boquett
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Martin Maiers
- CIBMTR (Center for International Blood and Marrow Transplant Research), NMDP, Minneapolis, MN, USA
| | - Jill A Hollenbach
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
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D'Costa J, Chibo D, Soloczynskyj K, Batty M, Sameer R, Lee E, Tran T, Mavroulis D, Gooey M, Williams E, Jackson K. Evaluation and comparison of three high throughput assays (Alinity m CMV, Aptima CMV Quant and cobas CMV) for quantifying CMV DNA in plasma samples. J Virol Methods 2025; 332:115068. [PMID: 39551443 DOI: 10.1016/j.jviromet.2024.115068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 10/23/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) can cause symptomatic CMV syndrome or tissue-invasive CMV disease in immunocompromised individuals, including solid-organ transplant and hematopoietic stem cell transplant recipients. In these populations, monitoring of CMV load is essential, assessing both risk of disease and response to antiviral therapy. High throughput commercial assays are currently available for CMV quantitation, but they are often evaluated independently, with few studies comparing these assays. This study evaluated CMV quantitative assays for use with the Roche cobas 6800, Abbott Alinity m and Hologic Panther platforms using stored patient plasma. METHODS Analytical evaluation was performed using the 1st WHO international standard for human CMV for Nucleic Acid Amplification Techniques (cobas and Alinity m) or the Hologic CMV QC Calibrator 6 (Aptima). Parallel testing of 136 clinical plasma samples was performed across the three platforms. RESULTS Linearity for each assay ranged from 98.6 % to 99.96 % and precision and limit of quantitation were as expected with little variation between platforms. 136 clinical plasma samples were evaluated with similar agreement observed between each assay. The greatest positive agreement was between the Aptima Quant and Alinity m assays (95.6 %, 95 % CI 89-98.6 %) and the lowest between the Aptima Quant and cobas assays (94.1 %, 87.4-97.5 %). CONCLUSIONS All assays were sensitive and accurate when quantifying CMV, and performance across all 3 assays was comparable for monitoring CMV viral loads in patient plasma.
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Affiliation(s)
- Jodie D'Costa
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia.
| | - Doris Chibo
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Katherine Soloczynskyj
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Mitchell Batty
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Rizmina Sameer
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Elaine Lee
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Thomas Tran
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Dimi Mavroulis
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Megan Gooey
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Eloise Williams
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Melbourne 3000, Australia
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Cabanilla MG, Dauenhauer A, St John B, Hill D, Larson J. Taming the transplant troll: Exploring racial and ethnic disparities in cytomegalovirus infection among kidney transplant patients. PLoS One 2025; 20:e0317383. [PMID: 39879165 PMCID: PMC11778782 DOI: 10.1371/journal.pone.0317383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) infection poses a significant risk to kidney transplant recipients. This study investigated CMV disease incidence, outcomes, and management challenges in racial and ethnic minority populations following kidney transplantation. METHODS This single-center, mixed-methods study included a retrospective cohort analysis of kidney transplant recipients (n = 58) and qualitative surveys of healthcare providers. Patients were categorized as minorities (n = 49) or non-Hispanic whites (n = 9). The primary outcome was CMV disease incidence. Secondary outcomes included graft failure, mortality, and identification of management barriers. RESULTS The cumulative incidence of CMV disease was higher in minorities than in non-Hispanic whites (12.3% vs. 0%, p = 0.58), although the difference was not statistically significant. All graft failures (8.6%, n = 5) occurred in the minority group. Although not statistically significant, all-cause mortality was higher in the minority group (24.5% vs. 11.1%, p = 0.54), with 46.2% of the deaths occurring within 90 days of CMV diagnosis. Qualitative analysis revealed challenges in diagnosis, treatment-related side effects, medication costs, and insurance barriers. The providers emphasized the importance of interdisciplinary collaboration and standardized protocols. CONCLUSION While limited by the small sample size, this study highlights potential disparities in the incidence and outcomes of CMV disease among minority kidney transplant recipients, suggesting that barriers in care and access may contribute to these differences. These hypothesis-generating findings underscore the need for larger multicenter studies to validate these patterns and to inform targeted strategies that may reduce inequities in post-transplant outcomes.
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Affiliation(s)
- M. Gabriela Cabanilla
- Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Ashlee Dauenhauer
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Briana St John
- Department of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
| | - Deirdre Hill
- University of New Mexico School of Medicine, Albuquerque, NM, United States of America
| | - Joshua Larson
- Division of Transplant Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States of America
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Savitz J, McKinney BA, Meier TB, Zheng H, Ford BN, Yolken RH, Teague TK, Cole SW. Nuclear factor kappa-B cell (NF-κB), interferon regulatory Factor, and glucocorticoid receptor pathway activation in major depressive Disorder: The role of cytomegalovirus infection. Brain Behav Immun 2025; 123:1052-1060. [PMID: 39532200 PMCID: PMC11624063 DOI: 10.1016/j.bbi.2024.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024] Open
Abstract
Altered activity of major immunoregulatory pathways has been reported in major depressive disorder (MDD) and is thought to underlie the elevations in circulating inflammatory mediators present in a subgroup of patients. However, the drivers of these changes in gene expression remain unclear. One potential modulator of immune function is viral infection. Here we examined the relationship between cytomegalovirus (CMV), a common herpesvirus, that has been shown to be a pathological cofactor in inflammatory disorders, and activity of key coordinators of the innate inflammatory response in MDD. We used RNAseq to characterize gene expression differences in in 79 unmedicated individuals with MDD and 80 healthy controls (HCs). A well-established bioinformatic strategy was used to quantify transcription control pathway activity based on the relative prevalence of pre-specified transcription factor-binding motifs in the promoters of differentially expressed genes. The main aim was to characterize diagnostic differences in immunoregulatory pathway activity and determine if these were related to CMV serostatus or antibody titer (viral reactivation). Significantly increased activity of interferon regulatory factor 1 (IRF1) and nuclear factor kappa-B cell (NF-κB) pathways was observed in the MDD group compared with HCs. Transcript Origin Analyses using cell-specific reference transcriptomes indicated that the MDD-associated transcriptome changes derived primarily from myeloid lineage immune cells (classical and non-classical monocytes). A more modest MDD-associated upregulation of glucocorticoid receptor (GR) pathway activity was also present. CMV infection/activity across the combined MDD and HC groups was weakly related to GR pathway activation but not to IRF1 and NF-κB activity; the most salient signature of CMV was activation and/or expansion of the CD8+ T-cell population. The elevated MDD-associated NF-κB (but not IRF1) activity was markedly attenuated after controlling for CMV antibody titer or for CD8+ T-cell prevalence. At least some of the NF-κB signal in MDD may be attributable to the cellular immune response to CMV, suggesting that CMV infection may be one of several pathways contributing to inflammation in depression. The pronounced activation of the antiviral IRF-1 pathway in MDD suggests the contribution of viral processes although this specific antiviral effect was not specific to CMV.CMV may indirectly drive interferon responses by impairing T-cell control of other viral infections.
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Affiliation(s)
- Jonathan Savitz
- Laureate Institute for Brain Research, Tulsa OK, USA; Oxley College of Health and Natural Sciences, The University of Tulsa, Tulsa OK, USA.
| | - Brett A McKinney
- Department of Mathematics and Computer Science, The University of Tulsa, Tulsa, OK, USA
| | - Timothy B Meier
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI USA
| | - Haixia Zheng
- Laureate Institute for Brain Research, Tulsa OK, USA; Oxley College of Health and Natural Sciences, The University of Tulsa, Tulsa OK, USA
| | - Bart N Ford
- Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
| | - Robert H Yolken
- Stanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - T Kent Teague
- Department of Surgery, University of Oklahoma School of Community Medicine, Tulsa, OK, USA; Department of Psychiatry, University of Oklahoma School of Community Medicine, Tulsa, OK, USA; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
| | - Steve W Cole
- University of California, Los Angeles, Cousins Center for Psychoneuroimmunology, Los Angeles, CA, USA; University of California, Los Angeles, David Geffen School of Medicine, Department of Psychiatry and Biobehavioral Sciences, Los Angeles, CA, USA
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10
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Chen M, Ke C, Huang Y. Herpes virus reactivation induced by abrocitinib: A real-world pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. Diagn Microbiol Infect Dis 2024; 110:116546. [PMID: 39340963 DOI: 10.1016/j.diagmicrobio.2024.116546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/02/2024] [Accepted: 09/22/2024] [Indexed: 09/30/2024]
Abstract
PURPOSE Large real-world studies evaluating the association between abrocitinib and herpes virus reactivation are lacking. This objective of investigation was to delineate the characteristics of abrocitinib-associated herpes virus reactivation through the FDA Adverse Event Reporting System. RESULTS Total of 56 reports were distinctly associated with herpes virus reactivation, with serious adverse events accounting for 67.86 %. Several noteworthy findings emerged: (1) female is associated with relatively high risk of herpes virus reactivation. (2) The proportion of herpes virus reactivation cases reported from the United States has decreased significantly compared to the overall reports. (3) The inclusion of dupilumab in combination regimens appeared to be associated with a comparatively reduced risk of herpes virus reactivation, while the risk of regimens containing baricitinib was increased. CONCLUSION These findings will help us to identify risk factors for herpes virus activation in atopic dermatitis patients, and facilitate the implementation of targeted measures to prevent and mitigate herpes virus activation.
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Affiliation(s)
- Maohua Chen
- Department of Pharmacy, Pingtan Comprehensive Experimental Area Hospital, Pingtan Comprehensive Experimental Area, Fuzhou, 350400, China
| | - Chengjie Ke
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Yaping Huang
- Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, NO.134 Dongjie Street, Fuzhou, 350001, Fujian, China.
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11
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Razonable RR. Cytomegalovirus Infection After Solid Organ Transplantation: How I Use Cell-Mediated Immune Assays for Management. Viruses 2024; 16:1781. [PMID: 39599895 PMCID: PMC11598960 DOI: 10.3390/v16111781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/07/2024] [Accepted: 11/09/2024] [Indexed: 11/29/2024] Open
Abstract
INTRODUCTION The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic pathogen that occurs as a result of impaired pathogen-specific immunity, laboratory assays that measure CMV-specific immune responses may be useful in assisting clinicians in its management. METHODS AND RESULTS The author summarizes the evolving and emerging data on the clinical utility of assays that quantify cell-mediated immune responses to CMV in SOT recipients. The majority of publications are observational studies that demonstrate that a lack or deficiency in CMV-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation, or recurrent CMV after transplantation. A few prospective interventional studies have utilized CMV-specific cell-mediated immune assays in guiding the duration of antiviral prophylaxis among CMV-seropositive SOT recipients. Likewise, CMV-specific cell-mediated immunity assays have been suggested to inform the need for secondary antiviral prophylaxis and immunologic optimization to prevent CMV relapse after treatment. CONCLUSIONS CMV-specific cell-mediated immune assays are emerging to assist transplant clinicians in predicting a patient's risk of CMV after transplantation, and these assays have been utilized to individualize the approach to CMV prevention and treatment. The author suggests the conduct of more interventional studies to further solidify the role of CMV-specific cell-mediated immune assays in routine clinical practice.
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Affiliation(s)
- Raymund R Razonable
- Division of Infectious Diseases and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA
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12
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Razonable RR. Pathogen-specific cell-mediated immunity to guide the management of cytomegalovirus in solid organ transplantation: state of the art clinical review. Expert Rev Clin Immunol 2024; 20:1367-1380. [PMID: 39039915 DOI: 10.1080/1744666x.2024.2384060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/21/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation, with significant impact on morbidity and long-term survival. Despite advances in diagnostics and therapeutics, the management of CMV remains very challenging. AREAS COVERED This article reviews emerging data on the clinical utility of laboratory assays that quantify cell-mediated immune responses to CMV. Observational studies have consistently demonstrated that a deficiency in pathogen-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation or recurrent CMV after transplantation. A limited number of interventional studies have recently investigated cell-mediated immune assays in guiding the prevention and treatment of CMV infection after solid organ transplantation. EXPERT OPINION The pathogenesis and outcome of CMV after solid organ transplantion reflect the interplay between viral replication and CMV-specific immune reconstitution. Research in CMV-specific cell-mediated immunity paved way for the development of several laboratory assays that may assist clinicians in predicting the risk of CMV after transplantation, individualize the approach to CMV disease prevention, guide the need and duration of treatment of CMV infection, and predict the risk of relapse after treatment. More interventional studies are needed to further solidify the role of cell-mediated immune assays in various clinical situations after transplantation.
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Affiliation(s)
- Raymund R Razonable
- Division of Public Health, Infectious Diseases and Occupational Medicine, and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA
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13
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Xin Y, Zhou Y. Association between cytomegalovirus infection and dyslipidemia in US: an NHANES analysis. Eur J Clin Microbiol Infect Dis 2024; 43:1883-1897. [PMID: 39066967 DOI: 10.1007/s10096-024-04905-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection is widely prevalent worldwide, which may have relationship with dyslipidemia. The aim of this study is to explore the association between CMV infection and dyslipidemia. METHODS The total observed population of this study included 14,163 participants aged 6-49 years from 1999 to 2004 National Health and Nutritional Examination Surveys (NHANES). Immunoglobulin G (IgG) levels and four lipid parameters (triglyceride, low density lipoprotein-cholesterol (LDL-C), total cholesterol, and high density lipoprotein-cholesterol (HDL-C)) were analyzed by performing multiple logistic regression and subgroup analysis. RESULTS The median values of triglycerides, LDL-C and total cholesterol levels in the CMV positive group were higher than those in CMV negative group while a lower median value of HDL-C existed in positive group. After controlling for potential confounders (sex, age, race, country of birth, education, poverty-to-income ratio(PIR)), a close association between CMV infection and low HDL-C was observed, which persisted in the men aged 30-49 and women aged 12-19, 30-49. CONCLUSIONS CMV infection is related to dyslipidemia, and this association is more significant in the serum HDL-C. Further cohort studies and experimental evidences can be conducted to test this association and then guide clinical practice.
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Affiliation(s)
- Yiyang Xin
- Department of Pathogen Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Yun Zhou
- Department of Pathogen Biology, School of Basic Medical Sciences, Henan University, Kaifeng, China.
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14
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Abidi MZ, Lopez R, Arrigain S, Weinberg A, Kaplan B, McAdams-DeMarco M, Schold JD, Erlandson KM. Area-Level Social Deprivation and Cytomegalovirus Seropositivity at the Time of Solid Organ Transplant. JAMA Netw Open 2024; 7:e2437878. [PMID: 39374014 PMCID: PMC11581662 DOI: 10.1001/jamanetworkopen.2024.37878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/14/2024] [Indexed: 10/08/2024] Open
Abstract
Importance Cytomegalovirus (CMV) is associated with significant morbidity and mortality in solid organ transplant (SOT) recipients. The risk factors for CMV seropositivity in SOT recipients, including area-level social deprivation in the US, have not been fully characterized. Objective To (1) evaluate CMV seroprevalence, (2) assess the recipient characteristics associated with CMV seropositivity, and (3) assess the association of area-level social deprivation index (SDI) scores with pretransplant CMV serostatus. Design, Setting, and Participants This retrospective cross-sectional analysis of the Scientific Registry of Transplant Recipients database included all adult (aged ≥18 years) SOT recipients from January 1, 2008, to May 31, 2022. Data were analyzed from April 10 to October 25, 2023. Exposure Recipient characteristics and area-level SDI. Main Outcomes and Measures Multivariable generalized linear models were used to evaluate the association between (1) patient characteristics and CMV and (2) social deprivation (measured by SDI scores, which were assessed in quintiles, from lowest to highest) and CMV seropositivity. In addition, differences based on patient demographics and the transplanted organ(s) were evaluated. Results Among the 389 288 SOT recipients included in the analysis, mean (SD) age was 53.3 (13.0) years; 63.0% were male, 21.4% were Black, 15.2% were Hispanic White, 56.2% were non-Hispanic White, and 62.7% were CMV seropositive. The mean (SD) age was higher among CMV seropositive (54.0 [12.7] years) compared with CMV seronegative (52.0 [13.5] years) patients. Seropositivity for CMV was higher among women (69.9%) than men (58.5%) and among Black (74.8%) and Hispanic White (80.2%) patients compared with non-Hispanic White patients (50.4%). Seropositivity for CMV was highest among kidney (64.5%), liver (63.6%), and kidney and liver (66.2%) recipients. Greater SDI scores were associated with greater CMV seropositivity, ranging from 51.7% for the least deprived to 75.5% for the most deprived quintiles (P < .001), independent of age, sex, or race. Conclusions and Relevance In this cross-sectional study, an association between SDI and CMV seropositivity was observed among SOT recipients, independent of age, sex, or race and ethnicity. To optimize posttransplant outcomes in CMV seropositive recipients, efforts targeting prevention of CMV reactivation need to be prioritized in these higher-risk populations.
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Affiliation(s)
- Maheen Z. Abidi
- Division of Infectious Diseases, Department of Medicine, University of Colorado Denver School of Medicine
| | - Rocio Lopez
- Department of Surgery, University of Colorado Denver School of Medicine
- Colorado Center for Transplantation Care, Research and Education, Aurora
| | - Susana Arrigain
- Department of Surgery, University of Colorado Denver School of Medicine
- Colorado Center for Transplantation Care, Research and Education, Aurora
| | - Adriana Weinberg
- Division of Pediatric Infectious Diseases, Departments of Pediatrics, Medicine, and Pathology, University of Colorado Denver School of Medicine
| | - Bruce Kaplan
- Department of Surgery, University of Colorado Denver School of Medicine
- Colorado Center for Transplantation Care, Research and Education, Aurora
| | - Mara McAdams-DeMarco
- Department of Surgery, NYU Grossman School of Medicine and Langone Health, New York, New York
- Department of Population Health, NYU Grossman School of Medicine, New York, New York
| | - Jesse D. Schold
- Department of Surgery, University of Colorado Denver School of Medicine
- Colorado Center for Transplantation Care, Research and Education, Aurora
| | - Kristine M. Erlandson
- Division of Infectious Diseases, Department of Medicine, University of Colorado Denver School of Medicine
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15
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Johnson KE, Hernandez-Alvarado N, Blackstad M, Heisel T, Allert M, Fields DA, Isganaitis E, Jacobs KM, Knights D, Lock EF, Rudolph MC, Gale CA, Schleiss MR, Albert FW, Demerath EW, Blekhman R. Human cytomegalovirus in breast milk is associated with milk composition and the infant gut microbiome and growth. Nat Commun 2024; 15:6216. [PMID: 39043677 PMCID: PMC11266569 DOI: 10.1038/s41467-024-50282-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 07/03/2024] [Indexed: 07/25/2024] Open
Abstract
Human cytomegalovirus (CMV) is a highly prevalent herpesvirus that is often transmitted to the neonate via breast milk. Postnatal CMV transmission can have negative health consequences for preterm and immunocompromised infants, but any effects on healthy term infants are thought to be benign. Furthermore, the impact of CMV on the composition of the hundreds of bioactive factors in human milk has not been tested. Here, we utilize a cohort of exclusively breastfeeding full-term mother-infant pairs to test for differences in the milk transcriptome and metabolome associated with CMV, and the impact of CMV in breast milk on the infant gut microbiome and infant growth. We find upregulation of the indoleamine 2,3-dioxygenase (IDO) tryptophan-to-kynurenine metabolic pathway in CMV+ milk samples, and that CMV+ milk is associated with decreased Bifidobacterium in the infant gut. Our data indicate two opposing CMV-associated effects on infant growth; with kynurenine positively correlated, and CMV viral load negatively correlated, with infant weight-for-length at 1 month of age. These results suggest CMV transmission, CMV-related changes in milk composition, or both may be modulators of full-term infant development.
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Affiliation(s)
- Kelsey E Johnson
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
| | | | - Mark Blackstad
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Timothy Heisel
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Mattea Allert
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - David A Fields
- Department of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Katherine M Jacobs
- Department of Obstetrics, Gynecology and Women's Health, Division of Maternal-Fetal Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Dan Knights
- BioTechnology Institute, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Eric F Lock
- Division of Biostatistics and Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA
| | - Michael C Rudolph
- Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA
| | - Cheryl A Gale
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Mark R Schleiss
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Frank W Albert
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
| | - Ellen W Demerath
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA
| | - Ran Blekhman
- Section of Genetic Medicine, Division of Biological Sciences, University of Chicago, Chicago, IL, USA
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16
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Chen Y, Zhong J, Liu X, Liu Y, Zhou B, Ruan G, Zhao L, Shi X, Zhang L. Cytomegalovirus antigen-specific multi-cytokine immune responses in patients with rheumatic diseases under different cytomegalovirus infection status: A case-control study. Clin Chim Acta 2024; 561:119828. [PMID: 38909979 DOI: 10.1016/j.cca.2024.119828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/13/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
OBJECTIVE To explore Cytomegalovirus (CMV) antigen-specific multi-cytokine immune responses in patients with rheumatic disease (RD) under different CMV infection status. METHODS A total of 60 RD patients in our center from March 2023 to August 2023 were enrolled. The patients were divided into latent CMV infection and active CMV infection, the latter was classified as subclinical CMV infection or CMV disease based on presence or absence of symptoms related to CMV. Whole blood was collected and stimulated with QuantiFERON-CMV antigen. The levels of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17 and CXCL-2 in supernatant were measured by Luminex Assays. The receiver operating characteristic curve was used to evaluate the diagnostic accuracy of cytokine for distinguishing different CMV infection status. RESULTS The proportion of patients with severe lymphopenia was lowest in the latent CMV infection group, while there were no significant differences in medication usage in different CMV infection status. After stimulation with QF-CMV antigens, the levels of IFN-γ, TNF-α and IL-2 in the CMV disease group were significantly lower than those in the latent CMV infection group. CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia together provided the best discriminatory performance for distinguishing between latent and either active CMV infection patients (AUC = 0.854) or CMV disease patients (AUC = 0.935). CONCLUSION Noninvasive peripheral blood biomarkers (the combination of CMV antigen-specific IFN-γ, TNF-α levels and severe lymphopenia) may have the potential to diferentiate different status of CMV infection in RD population.
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Affiliation(s)
- Yan Chen
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingjing Zhong
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoqing Liu
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Clinical Epidemiology Unit, Peking Union Medical College, International Clinical Epidemiology Network, Beijing, China
| | - Ye Liu
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baotong Zhou
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guiren Ruan
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaochun Shi
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Lifan Zhang
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Clinical Epidemiology Unit, Peking Union Medical College, International Clinical Epidemiology Network, Beijing, China.
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17
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Arevalo JF, Beatson B. Surgery for Infectious Retinitis - When Medical Therapy Is Not Sufficient: The Moacyr E. Alvaro Pan-American Lecture 2023. Ocul Immunol Inflamm 2024; 32:541-549. [PMID: 36758250 DOI: 10.1080/09273948.2023.2174883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/05/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND Viral retinitis composes a group of infectious ocular diseases with poor prognoses. With the advent of antivirals and HAART, the treatment of these diseases has evolved and ocular outcomes have improved. However, even with prompt medical treatment, a significant number of patients will experience complications that require surgical intervention. While there has been an abundance of research examining the medical treatment of CMV retinitis and acute retinal necrosis, the research examining surgical outcomes of complications such as retinitis-associated retinal detachment is comparatively limited. METHODS Literature review. RESULTS In this review, we discuss the current literature examining treatment of CMV retinitis and acute retinal necrosis, with a focus on surgical management of complications such as retinal detachment. CONCLUSIONS Despite significant improvements in the medical treatment of CMV retinitis and ARN over the last three decades, vision-threatening complications such as retinal detachment are relatively common and require surgical management via PPV, laser photocoagulation, and intraocular gas or silicone oil tamponade.
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Affiliation(s)
- J Fernando Arevalo
- Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, Maryland, USA
| | - Bradley Beatson
- Johns Hopkins University School of Medicine, Wilmer Eye Institute, Baltimore, Maryland, USA
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18
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Lantos PM, Gantt S, Janko M, Dionne F, Permar SR, Fowler K. A Geographically Weighted Cost-effectiveness Analysis of Newborn Cytomegalovirus Screening. Open Forum Infect Dis 2024; 11:ofae311. [PMID: 38933739 PMCID: PMC11200186 DOI: 10.1093/ofid/ofae311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Background Early identification of newborns with congenital cytomegalovirus (CMV) is necessary to provide antiviral therapy and other interventions that can improve outcomes. Prior research demonstrates that universal newborn CMV screening would be the most cost-effective approach to identifying newborns who are infected. CMV is not uniformly prevalent, and it is uncertain whether universal screening would remain cost-effective in lower-prevalence neighborhoods. Our aim was to identify geographic heterogeneity in the cost-effectiveness of universal newborn CMV screening by combining a geospatial analysis with a preexisting cost-effectiveness analysis. Methods This study used the CMV testing results and zip code location data of 96 785 newborns in 7 metropolitan areas who had been tested for CMV as part of the CMV and Hearing Multicenter Screening study. A hierarchical bayesian generalized additive model was constructed to evaluate geographic variability in the odds of CMV. The zip code-level odds of CMV were then used to weight the results of a previously published model evaluating universal CMV screening vs symptom-targeted screening. Results The odds of CMV were heterogeneous over large geographic scales, with the highest odds in the southeastern United States. Universal screening was more cost-effective and afforded more averted cases of severe hearing loss than targeted testing. Universal screening remained the most cost-effective option even in areas with the lowest CMV prevalence. Conclusions Universal newborn CMV screening is cost-effective regardless of underlying CMV prevalence and is the preferred strategy to reduce morbidity from congenital CMV.
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Affiliation(s)
- Paul M Lantos
- Divisions of Pediatric Infectious Diseases, General Internal Medicine, and Occupational and Environmental Medicine, School of Medicine, Duke University, Durham, North Carolina, USA
- Duke Global Health Institute, Durham, North Carolina, USA
| | - Soren Gantt
- Departments of Microbiology, Infectious Diseases & Immunology and Pediatrics, Université de Montréal, Montreal, Quebec, Canada
| | - Mark Janko
- Duke Global Health Institute, Durham, North Carolina, USA
| | - Francois Dionne
- Centre for Clinical Epidemiology and Evaluation, Vancouver, British Columbia, Canada
| | - Sallie R Permar
- Department of Pediatrics, Weill Cornell Medicine, New York, New York, USA
| | - Karen Fowler
- Department of Pediatrics, University of Alabama, Birmingham, Alabama, USA
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19
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McGuirk M, Shahzad M, Amin MK, Khan MA, Bellman P, Mudaranthakam DP, DeJarnette S, Lutfi F, Ahmed N, Bansal R, Abdelhakim H, Gorsline C, Shoemaker DM, Abdallah AO, Shune L, Abhyankar SH, Singh AK, McGuirk JP, Mushtaq MU. Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience. Transpl Immunol 2024; 84:102039. [PMID: 38513813 DOI: 10.1016/j.trim.2024.102039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.
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Affiliation(s)
- Matthew McGuirk
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Moazzam Shahzad
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Muhammad Kashif Amin
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Muhammad Atif Khan
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Polina Bellman
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Dinesh Pal Mudaranthakam
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Shaun DeJarnette
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Forat Lutfi
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Nausheen Ahmed
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Rajat Bansal
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Haitham Abdelhakim
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Chelsea Gorsline
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Dennis Matthew Shoemaker
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Al-Ola Abdallah
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Leyla Shune
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Sunil H Abhyankar
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Anurag K Singh
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Joseph P McGuirk
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America
| | - Muhammad Umair Mushtaq
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America.
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20
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Reed RG, Hillmann AR, Presnell SR, Al-Attar A, Lutz CT, Segerstrom SC. Lifespan Socioeconomic Context Is Associated With Cytomegalovirus and Late-Differentiated CD8 + T and Natural Killer Cells: Initial Results in Older Adults. Psychosom Med 2024; 86:443-452. [PMID: 37982534 PMCID: PMC11096264 DOI: 10.1097/psy.0000000000001267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
OBJECTIVE Lower socioeconomic status (SES) can accelerate immune aging; however, it is unknown whether and how lifespan socioeconomic context (SEC)-the relative wealth and quality of the communities an individual lives in across their lifespan-impacts immune aging. We examined the effects of childhood and adulthood SEC on late-differentiated immune cells and investigated the mediating and moderating role of cytomegalovirus (CMV), a key driver of immune aging. METHODS Adults 60 years and older ( N = 109) reported their addresses from birth to age 60 years, which were coded for county-level employment, education, and income to construct a latent SEC variable, averaged across ages 0 to 18 years (childhood SEC) and 19 to 60 years (adulthood SEC). Blood was drawn semiannually for 5 years for CMV serostatus and flow cytometry estimates of late-differentiated CD8 + T and natural killer cells. Models were adjusted for chronological age, time, sex, and individual SES (current income and education). RESULTS Lower childhood SEC was associated with higher percentages of late-differentiated CD8 + T and natural killer cells via CMV seropositivity (indirect effects, p values = .015-.028). In addition, an interaction between CMV serostatus and SEC on CD8 + T-cell aging ( p = .049) demonstrated that adulthood SEC was negatively associated with immune aging among CMV- but not CMV+ adults. CONCLUSIONS Beyond current SES, SEC related to immune aging in distinct patterns by lifespan phase. Lower childhood SEC importantly may influence who acquires CMV, which in turn predicts higher levels of immune aging, whereas higher adulthood SEC was protective against immune aging among CMV- older adults. These initial results need to be explored in larger samples.
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Affiliation(s)
| | | | - Steven R. Presnell
- Departments of Chemistry and of Pathology and Laboratory Medicine, University of Kentucky
| | - Ahmad Al-Attar
- Department of Hematopathology, University of Massachusetts Medical Center
| | - Charles T. Lutz
- Departments of Microbiology, Immunology, and Molecular Genetics and of Pathology and Laboratory Medicine, University of Kentucky
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21
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James LM, Tsilibary EP, Wanberg EJ, Georgopoulos AP. Negative Association of Cognitive Performance With Blood Serum Neurotoxicity and Its Modulation by Human Herpes Virus 5 (HHV5) Seropositivity in Healthy Women. Neurosci Insights 2024; 19:26331055241258436. [PMID: 38827247 PMCID: PMC11143810 DOI: 10.1177/26331055241258436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/15/2024] [Indexed: 06/04/2024] Open
Abstract
Identification of early influences on cognitive decline is of paramount importance in order to stem the impacts of decrements in cognitive functioning and to potentially intervene. Thus, here we focused on 132 healthy adult women (age range 26-98 years) to (a) determine whether factors circulating in serum may exert neurotoxic effects in vitro, (b) evaluate associations between serum neurotoxicity and cognitive performance, and (c) assess the influence of human herpes virus (HHV) seroprevalence and other factors on apoptosis and cognitive performance. The results documented that the addition of serum from healthy adult women to neural cell cultures resulted in apoptosis, indicating the presence of circulating neurotoxic factors in the serum. Furthermore, apoptosis increased with age, and was associated with decreased cognitive performance. Stepwise regression evaluating the influence of 6 HHVs on apoptosis and cognitive function revealed that only HHV5 (cytomegalovirus; CMV) seropositivity was significantly associated with apoptosis and cognitive decline, controlling for age. These findings document neurotoxic effects of serum from healthy women across the adult lifespan and suggest a unique detrimental influence associated with CMV seropositivity.
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Affiliation(s)
- Lisa M James
- The Healthy Brain Aging Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Effie-Photini Tsilibary
- The Healthy Brain Aging Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Erik J Wanberg
- The Healthy Brain Aging Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, USA
| | - Apostolos P Georgopoulos
- The Healthy Brain Aging Group, Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN, USA
- Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA
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22
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Payne H, Barnabas S. "Congenital cytomegalovirus in Sub-Saharan Africa-a narrative review with practice recommendations". Front Public Health 2024; 12:1359663. [PMID: 38813410 PMCID: PMC11134569 DOI: 10.3389/fpubh.2024.1359663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 04/24/2024] [Indexed: 05/31/2024] Open
Abstract
Cytomegalovirus (CMV) is the most common cause of congenital infection internationally, occurring in 0.67% of births, and increasingly recognised as a major public health burden due to the potential for long-term neurodevelopmental and hearing impairment. This burden includes estimates of 10% of childhood cerebral palsy and up to 25% of childhood deafness. In Sub-Saharan Africa, where CMV-seroprevalence is almost ubiquitous, prevalence of congenital CMV (cCMV) is higher than the global average, and yet there is a dearth of research and initiatives to improve recognition, diagnosis and treatment. This narrative review outlines the epidemiology and clinical presentation of cCMV, discusses issues of case identification and treatment in Sub-Saharan Africa, and recommends a framework of strategies to address these challenges. Considering the significant burden of cCMV disease in this setting, it is undoubtably time we embark upon improving diagnosis and care for these infants.
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Affiliation(s)
- Helen Payne
- Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
- Section of Paediatric Infectious Disease, Imperial College London, London, United Kingdom
| | - Shaun Barnabas
- Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
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23
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Yang NY, Hsieh AYY, Chen Z, Campbell AR, Gadawska I, Kakkar F, Sauve L, Bitnun A, Brophy J, Murray MCM, Pick N, Krajden M, Côté HCF, CIHR Team on Cellular Aging and HIV Comorbidities in Women and Children (CARMA). Chronic and Latent Viral Infections and Leukocyte Telomere Length across the Lifespan of Female and Male Individuals Living with or without HIV. Viruses 2024; 16:755. [PMID: 38793637 PMCID: PMC11125719 DOI: 10.3390/v16050755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/01/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL). METHODS Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling. RESULTS The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3-4 viruses (vs. 0-2) was associated with a shorter LTL. CONCLUSIONS Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.
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Affiliation(s)
- Nancy Yi Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Anthony Y. Y. Hsieh
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Zhuo Chen
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 2A1, Canada
| | - Amber R. Campbell
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
- Women’s Health Research Institute, British Columbia Women’s Hospital and Health Centre, Vancouver, BC V6H 2N9, Canada; (L.S.); (M.C.M.M.)
- Oak Tree Clinic, BC Women’s Hospital and Health Centre, Vancouver, BC V5Z 0C9, Canada
| | - Izabella Gadawska
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
| | - Fatima Kakkar
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada;
| | - Laura Sauve
- Women’s Health Research Institute, British Columbia Women’s Hospital and Health Centre, Vancouver, BC V6H 2N9, Canada; (L.S.); (M.C.M.M.)
- Oak Tree Clinic, BC Women’s Hospital and Health Centre, Vancouver, BC V5Z 0C9, Canada
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Ari Bitnun
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada;
| | - Jason Brophy
- Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada;
| | - Melanie C. M. Murray
- Women’s Health Research Institute, British Columbia Women’s Hospital and Health Centre, Vancouver, BC V6H 2N9, Canada; (L.S.); (M.C.M.M.)
- Oak Tree Clinic, BC Women’s Hospital and Health Centre, Vancouver, BC V5Z 0C9, Canada
- Department of Medicine, Division of Infectious Diseases, University of British Columbia Faculty of Medicine, Vancouver, BC V5Z 1M9, Canada
| | - Neora Pick
- Women’s Health Research Institute, British Columbia Women’s Hospital and Health Centre, Vancouver, BC V6H 2N9, Canada; (L.S.); (M.C.M.M.)
- Oak Tree Clinic, BC Women’s Hospital and Health Centre, Vancouver, BC V5Z 0C9, Canada
- Department of Medicine, Division of Infectious Diseases, University of British Columbia Faculty of Medicine, Vancouver, BC V5Z 1M9, Canada
| | - Mel Krajden
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
- British Columbia Center for Disease Control, Vancouver, BC V5Z 4R4, Canada
| | - Hélène C. F. Côté
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; (N.Y.Y.); (A.Y.Y.H.); (M.K.)
- Centre for Blood Research, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Women’s Health Research Institute, British Columbia Women’s Hospital and Health Centre, Vancouver, BC V6H 2N9, Canada; (L.S.); (M.C.M.M.)
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24
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Vernooij RW, Michael M, Ladhani M, Webster AC, Strippoli GF, Craig JC, Hodson EM. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev 2024; 5:CD003774. [PMID: 38700045 PMCID: PMC11066972 DOI: 10.1002/14651858.cd003774.pub5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
BACKGROUND The risk of cytomegalovirus (CMV) infection in solid organ transplant recipients has resulted in the frequent use of prophylaxis to prevent the clinical syndrome associated with CMV infection. This is an update of a review first published in 2005 and updated in 2008 and 2013. OBJECTIVES To determine the benefits and harms of antiviral medications to prevent CMV disease and all-cause death in solid organ transplant recipients. SEARCH METHODS We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 5 February 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs comparing antiviral medications with placebo or no treatment, comparing different antiviral medications or different regimens of the same antiviral medications for CMV prophylaxis in recipients of any solid organ transplant. Studies examining pre-emptive therapy for CMV infection are studied in a separate review and were excluded from this review. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility, risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS This 2024 update found four new studies, bringing the total number of included studies to 41 (5054 participants). The risk of bias was high or unclear across most studies, with a low risk of bias for sequence generation (12), allocation concealment (12), blinding (11) and selective outcome reporting (9) in fewer studies. There is high-certainty evidence that prophylaxis with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment is more effective in preventing CMV disease (19 studies: RR 0.42, 95% CI 0.34 to 0.52), all-cause death (17 studies: RR 0.63, 95% CI 0.43 to 0.92), and CMV infection (17 studies: RR 0.61, 95% CI 0.48 to 0.77). There is moderate-certainty evidence that prophylaxis probably reduces death from CMV disease (7 studies: RR 0.26, 95% CI 0.08 to 0.78). Prophylaxis reduces the risk of herpes simplex and herpes zoster disease, bacterial and protozoal infections but probably makes little to no difference to fungal infection, acute rejection or graft loss. No apparent differences in adverse events with aciclovir, ganciclovir or valaciclovir compared with placebo or no treatment were found. There is high certainty evidence that ganciclovir, when compared with aciclovir, is more effective in preventing CMV disease (7 studies: RR 0.37, 95% CI 0.23 to 0.60). There may be little to no difference in any outcome between valganciclovir and IV ganciclovir compared with oral ganciclovir (low certainty evidence). The efficacy and adverse effects of valganciclovir or ganciclovir were probably no different to valaciclovir in three studies (moderate certainty evidence). There is moderate certainty evidence that extended duration prophylaxis probably reduces the risk of CMV disease compared with three months of therapy (2 studies: RR 0.20, 95% CI 0.12 to 0.35), with probably little to no difference in rates of adverse events. Low certainty evidence suggests that 450 mg/day valganciclovir compared with 900 mg/day valganciclovir results in little to no difference in all-cause death, CMV infection, acute rejection, and graft loss (no information on adverse events). Maribavir may increase CMV infection compared with ganciclovir (1 study: RR 1.34, 95% CI: 1.10 to 1.65; moderate certainty evidence); however, little to no difference between the two treatments were found for CMV disease, all-cause death, acute rejection, and adverse events at six months (low certainty evidence). AUTHORS' CONCLUSIONS Prophylaxis with antiviral medications reduces CMV disease and CMV-associated death, compared with placebo or no treatment, in solid organ transplant recipients. These data support the continued routine use of antiviral prophylaxis in CMV-positive recipients and CMV-negative recipients of CMV-positive organ transplants.
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Affiliation(s)
- Robin Wm Vernooij
- Department of Nephrology and Hypertension and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
| | - Mini Michael
- Division of Pediatric Nephrology, Baylor College of Medicine, Houston, TX, USA
| | - Maleeka Ladhani
- Nephrology, Lyell McEwin Hospital, Elizabeth Vale, Australia
| | - Angela C Webster
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Centre for Transplant and Renal Medicine, Westmead Millennium Institute, The University of Sydney at Westmead, Westmead, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Elisabeth M Hodson
- Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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25
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Jankovic M, Knezevic T, Tomic A, Milicevic O, Jovanovic T, Djunic I, Mihaljevic B, Knezevic A, Todorovic-Balint M. Human Cytomegalovirus Oncoprotection across Diverse Populations, Tumor Histologies, and Age Groups: The Relevance for Prospective Vaccinal Therapy. Int J Mol Sci 2024; 25:3741. [PMID: 38612552 PMCID: PMC11012084 DOI: 10.3390/ijms25073741] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/18/2024] [Accepted: 03/22/2024] [Indexed: 04/14/2024] Open
Abstract
The oncogenicity of the human cytomegalovirus (CMV) is currently being widely debated. Most recently, mounting clinical evidence suggests an anti-cancer effect via CMV-induced T cell-mediated tumor destruction. However, the data were mostly obtained from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. Our study examined the correlation between country-specific CMV seroprevalence (across 73 countries) and the age-standardized incidence rate (of 34 invasive tumors). The populations studied were stratified according to decadal age periods as the immunologic effects of CMV seropositivity may depend upon age at initial infection. The International Agency for Research on Cancer of the World Health Organization (IARC WHO) database was used. The multivariate linear regression analysis revealed a worldwide inverse correlation between CMV seroprevalence and the incidences of 62.8% tumors. Notably, this inverse link persists for all cancers combined (Spearman's ρ = -0.732, p < 0.001; β = -0.482, p < 0.001, adjusted R2 = 0.737). An antithetical and significant correlation was also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this oncopreventive phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, additionally supporting the idea of a common underlying mechanism-CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, in-depth investigation of host-virus interactions is still warranted.
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Affiliation(s)
- Marko Jankovic
- Department of Virology, Institute of Microbiology and Immunology, 1 Dr Subotica Street, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
| | - Tara Knezevic
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
| | - Ana Tomic
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
| | - Ognjen Milicevic
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
- Institute of Medical Statistics and Informatics, 15 Dr Subotica Street, 11000 Belgrade, Serbia
| | - Tanja Jovanovic
- Institute for Biocides and Medical Ecology, 16 Trebevicka Street, 11000 Belgrade, Serbia;
| | - Irena Djunic
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
- Clinic of Hematology, University Clinical Centre of Serbia, 2 Dr Koste Todorovica Street, 11000 Belgrade, Serbia
| | - Biljana Mihaljevic
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
- Clinic of Hematology, University Clinical Centre of Serbia, 2 Dr Koste Todorovica Street, 11000 Belgrade, Serbia
| | - Aleksandra Knezevic
- Department of Virology, Institute of Microbiology and Immunology, 1 Dr Subotica Street, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
| | - Milena Todorovic-Balint
- Faculty of Medicine, University of Belgrade, 8 Dr Subotica Street, 11000 Belgrade, Serbia; (T.K.); (A.T.); (O.M.); (I.D.); (B.M.); (M.T.-B.)
- Clinic of Hematology, University Clinical Centre of Serbia, 2 Dr Koste Todorovica Street, 11000 Belgrade, Serbia
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26
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Hussein K, Shanley R, Schleiss MR. Exploring health disparities in congenital CMV (cCMV): a study in a Somali-American community to assess awareness of cCMV and facilitate understanding of universal cCMV screening. DISCOVER SOCIAL SCIENCE AND HEALTH 2024; 4:16. [PMID: 38694881 PMCID: PMC11062319 DOI: 10.1007/s44155-024-00070-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 02/29/2024] [Indexed: 05/04/2024]
Abstract
Background Congenital cytomegalovirus (cCMV) disproportionately impacts black and multiracial infants. While there have been strides made to address this health disparity, strategies to increase awareness and knowledge of cCMV have not been investigated in a Somali community. Methods Two survey study strategies (in-person and online), consisting of a pre-survey test, educational intervention, and a post-survey, were designed to gauge knowledge and perceptions about cCMV among Somali women aged 18 to 40 years old. Results 96 respondents partook in the online module, and 15 in the in-person event. On recruitment, < 45% of women were aware of cCMV. Following the pre-intervention survey, educational modules were conducted, and the survey repeated. For statistical comparisons, a point was assigned for each correct survey query, and the mean of correct responses tabulated for pre- and post-surveys. In the online intervention, mean scores changed from 55 to 87% (paired t-test, p = 0.001), whereas in the in-person intervention, mean scores changed from 65 to 87% (paired t-test, p = 0.007), demonstrating enhanced cCMV awareness upon completion of both interventions. Using multiple linear regression, the expected post-test score was 2% (95% CI [- 8%, 12%]) higher for the online module compared to the in-person module, adjusting for pre-test score. Conclusion Both interventions were successful in enhancing knowledge about cCMV in this population, although there was no evidence either intervention was substantially better than the other. Educational efforts will be critical in enhancing the trust required to facilitate diagnostic evaluation and treatment of newborns identified with cCMV in this high-risk population.
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Affiliation(s)
- Khadra Hussein
- University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55454, USA
| | - Ryan Shanley
- Biostatistics Core, University of Minnesota Clinical and Translational Science Institute, 717 Delaware Street SE, Minneapolis, MN 55414, USA
| | - Mark R. Schleiss
- Division of Pediatric Infectious Diseases, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA
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27
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Harrison MAA, Morris SL, Rudman GA, Rittenhouse DJ, Monk CH, Sakamuri SSVP, Mehedi Hasan M, Shamima Khatun M, Wang H, Garfinkel LP, Norton EB, Kim S, Kolls JK, Jazwinski SM, Mostany R, Katakam PVG, Engler-Chiurazzi EB, Zwezdaryk KJ. Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice. Brain Behav Immun 2024; 117:36-50. [PMID: 38182037 PMCID: PMC11914963 DOI: 10.1016/j.bbi.2023.12.033] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/21/2023] [Accepted: 12/23/2023] [Indexed: 01/07/2024] Open
Abstract
Risk factors contributing to dementia are multifactorial. Accumulating evidence suggests a role for pathogens as risk factors, but data is largely correlative with few causal relationships. Here, we demonstrate that intermittent murine cytomegalovirus (MCMV) infection of mice, alters blood brain barrier (BBB) permeability and metabolic pathways. Increased basal mitochondrial function is observed in brain microvessels cells (BMV) exposed to intermittent MCMV infection and is accompanied by elevated levels of superoxide. Further, mice score lower in cognitive assays compared to age-matched controls who were never administered MCMV. Our data show that repeated systemic infection with MCMV, increases markers of neuroinflammation, alters mitochondrial function, increases markers of oxidative stress and impacts cognition. Together, this suggests that viral burden may be a risk factor for dementia. These observations provide possible mechanistic insights through which pathogens may contribute to the progression or exacerbation of dementia.
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Affiliation(s)
- Mark A A Harrison
- Neuroscience Program, Tulane Brain Institute, Tulane University School of Science & Engineering, New Orleans, LA 70112, USA; Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sara L Morris
- Biomedical Sciences Program, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Grace A Rudman
- Department of Environmental Studies, Tulane University School of Liberal Arts, New Orleans, LA 70112, USA
| | - Daniel J Rittenhouse
- Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Center for Translational Research in Infection & Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Chandler H Monk
- Bioinnovation Program, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Siva S V P Sakamuri
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Md Mehedi Hasan
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Mst Shamima Khatun
- Tulane Center for Translational Research in Infection & Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hanyun Wang
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Lucas P Garfinkel
- Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Elizabeth B Norton
- Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Sangku Kim
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jay K Kolls
- Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Center for Translational Research in Infection & Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - S. Michal Jazwinski
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA; Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Ricardo Mostany
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Prasad V G Katakam
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Elizabeth B Engler-Chiurazzi
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA.
| | - Kevin J Zwezdaryk
- Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA 70112, USA.
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28
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Egorov AI, Griffin SM, Styles JN, Kobylanski J, Klein J, Wickersham L, Ritter R, Sams E, Hudgens EE, Wade TJ. Time outdoors and residential greenness are associated with reduced systemic inflammation and allostatic load. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 344:123408. [PMID: 38278402 DOI: 10.1016/j.envpol.2024.123408] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024]
Abstract
Contacts with nature are linked with reduced morbidity and mortality. Hypothesized pathways include relaxation, physical activity, and improved immune function. This cross-sectional study of 320 adults in central North Carolina assessed health benefits of residential greenness using allostatic load (AL) and systemic inflammation (INFL) indices, composite biomarker-based measures of physiological dysregulation and inflammation, respectively. Distance-to-residence weighted tree cover and vegetated land cover measures were estimated within 500 m of each residence; 37 biomarkers of immune, neuroendocrine, cardiovascular, and metabolic functions were dichotomized at distribution or health-based cut-offs. AL was calculated as a sum of potentially unhealthy values of all biomarkers; INFL was based on a subset of 18 immune biomarkers. Regression analysis used generalized additive models for Poisson-distributed outcome. An interquartile range (IQR) increase in tree cover was associated with 0.89 (95 % Confidence Limits 0.82; 0.97) and 0.90 (0.79; 1.03)-fold change in AL and INFL, respectively. Greater daily outdoor time was associated with reduced AL and INFL, while leisure screen time, problems with sleeping, and common chronic infections were linked with increased AL and INFL. Among 138 individuals spending more than 1 h outdoors daily, an IQR increase in tree cover was associated with 0.76 (0.67; 0.86) and 0.81 (0.65; 1.02)-fold changes in AL and INFL, respectively. Among individuals with residential tree cover above the 50th percentile, spending more than 3 h outdoors daily was associated with 0.54 (0.37; 0.78) and 0.28 (0.15; 0.54)-fold changes in AL and INFL, respectively, compared to spending less than 30 min outdoors; there were no significant effects in the low tree cover stratum. Consistent but weaker effects were observed for vegetated land cover. Interaction effects of tree and vegetative cover and time spent outdoors on AL and INFL were statistically significant. This biomarker-based approach can help to assess public health benefits of green spaces.
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Affiliation(s)
- Andrey I Egorov
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA.
| | - Shannon M Griffin
- Office of Research and Development, United States Environmental Protection Agency, Cincinnati, OH, USA
| | - Jennifer N Styles
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jason Kobylanski
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Jo Klein
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Lindsay Wickersham
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Rebecca Ritter
- ORAU Student Services Contractor, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Elizabeth Sams
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Edward E Hudgens
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
| | - Timothy J Wade
- Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, USA
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29
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Huh K, Lee SO, Kim J, Lee SJ, Choe PG, Kang JM, Yang J, Sung H, Kim SH, Moon C, Seok H, Shi HJ, Wi YM, Jeong SJ, Park WB, Kim YJ, Kim J, Ahn HJ, Kim NJ, Peck KR, Kim MS, Kim SI. Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation. Infect Chemother 2024; 56:101-121. [PMID: 38527780 PMCID: PMC10990892 DOI: 10.3947/ic.2024.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 03/27/2024] Open
Abstract
Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.
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Affiliation(s)
- Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang-Oh Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Jungok Kim
- Division of Infectious Diseases, Department of Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Su Jin Lee
- Division of Infectious Diseases, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea
| | - Pyoeng Gyun Choe
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Ji-Man Kang
- Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jaeseok Yang
- Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
| | - Heungsup Sung
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Si-Ho Kim
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Chisook Moon
- Division of Infectious Diseases, Department of Internal Medicine, Inje University Busan Paik Hospital, College of Medicine, Busan, Korea
| | - Hyeri Seok
- Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Korea University Medicine, Ansan, Korea
| | - Hye Jin Shi
- Division of Infectious Diseases, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Yu Mi Wi
- Division of Infectious Diseases, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Su Jin Jeong
- Division of Infectious Diseases, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Wan Beom Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Youn Jeong Kim
- Division of Infectious Diseases, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung Joon Ahn
- Department of Surgery, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Nam Joong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myoung Soo Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Il Kim
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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30
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Dremel SE, Tagawa T, Koparde VN, Hernandez-Perez C, Arbuckle JH, Kristie TM, Krug LT, Ziegelbauer JM. Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection. EMBO Rep 2024; 25:1541-1569. [PMID: 38263330 PMCID: PMC10933408 DOI: 10.1038/s44319-023-00051-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/25/2024] Open
Abstract
To globally profile circRNAs, we employ RNA-Sequencing paired with chimeric junction analysis for alpha-, beta-, and gamma-herpesvirus infection. We find circRNAs are, as a population, resistant to host shutoff. We validate this observation using ectopic expression assays of human and murine herpesvirus endoribonucleases. During lytic infection, four circRNAs are commonly induced across all subfamilies of human herpesviruses, suggesting a shared mechanism of regulation. We test one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs are upregulated by either interferon-β or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we find an interferon-stimulated circRNA, circRELL1, inhibits lytic Herpes Simplex Virus-1 infection. We previously reported circRELL1 inhibits lytic Kaposi sarcoma-associated herpesvirus infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape.
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Affiliation(s)
- Sarah E Dremel
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA
| | - Takanobu Tagawa
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA
| | - Vishal N Koparde
- CCR Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, 20892, USA
- Frederick National Laboratory for Cancer Research Advanced Biomedical Computational Sciences, Leidos Biomedical Research, Inc., Frederick, 21701, USA
| | | | - Jesse H Arbuckle
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892, USA
| | - Thomas M Kristie
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892, USA
| | - Laurie T Krug
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA
| | - Joseph M Ziegelbauer
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA.
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Dana Flanders W, Lally C, Dilley A, Diaz-Decaro J. Estimated cytomegalovirus seroprevalence in the general population of the United States and Canada. J Med Virol 2024; 96:e29525. [PMID: 38529529 DOI: 10.1002/jmv.29525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/20/2024] [Accepted: 02/29/2024] [Indexed: 03/27/2024]
Abstract
Seroprevalence data for cytomegalovirus (CMV), a widespread virus causing lifelong infection, vary widely, and contemporary data from the United States (US) and Canada are limited. Utilizing a modeling approach based on a literature review (conducted August, 2022) of data published since 2005, we determine age-, sex-, and country-specific CMV seroprevalence in the general US and Canadian populations. Sex-specific data were extracted by age categories, and a random-effects meta-regression model was used to fit the reported data (incorporating splines for the US). Seven studies reported US CMV seroprevalence (both sexes, aged 1‒89 years); all used National Health and Nutrition Examination Survey data. Due to limited population-based studies, Canadian estimates were modeled using other limited country data. In both countries, modeled seroprevalence estimates increased with age and were higher in females versus males (US: 49.0% vs. 41.6% at 18‒19 years; 61.5% vs. 50.0% at 38‒39 years; Canada: 23.7% vs. 13.7% at 18‒19 years; 32.6% vs. 22.6% at 38‒39 years). Notably, by young adulthood, one-half of US and one-quarter of Canadian females have acquired CMV. The observed differences in CMV seroprevalence in the US and Canada may partially reflect variations in general population characteristics.
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Affiliation(s)
- W Dana Flanders
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Epidemiologic Research & Methods, LLC, Southport, NC, USA
| | - Cathy Lally
- Epidemiologic Research & Methods, LLC, Southport, NC, USA
| | - Anne Dilley
- Epidemiologic Research & Methods, LLC, Southport, NC, USA
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32
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Magda G. Opportunistic Infections Post-Lung Transplantation: Viral, Fungal, and Mycobacterial. Infect Dis Clin North Am 2024; 38:121-147. [PMID: 38280760 DOI: 10.1016/j.idc.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
Opportunistic infections are a leading cause of lung transplant recipient morbidity and mortality. Risk factors for infection include continuous exposure of the lung allograft to the external environment, high levels of immunosuppression, impaired mucociliary clearance and decreased cough reflex, and impact of the native lung microbiome in single lung transplant recipients. Infection risk is mitigated through careful pretransplant screening of recipients and donors, implementation of antimicrobial prophylaxis strategies, and routine surveillance posttransplant. This review describes common viral, fungal, and mycobacterial infectious after lung transplant and provides recommendations on prevention and treatment.
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Affiliation(s)
- Gabriela Magda
- Columbia University Lung Transplant Program, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University Irving Medical Center, Columbia University Vagelos College of Physicians and Surgeons, 622 West 168th Street PH-14, New York, NY 10032, USA.
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33
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Mengjiao L, Yushan X, Yan L, Dawei C, Xiaojun Z, Yongjun W, Cuifen S, Jue X. Prevalence of transfusion-transmitted infections in hospitalized patients before transfusion and volunteer blood donors in Zhejiang Province, China. Infect Dis Now 2024; 54:104861. [PMID: 38316362 DOI: 10.1016/j.idnow.2024.104861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/07/2024]
Abstract
OBJECTIVES To assess the need for screening of transfusion-transmitted infections (TTIs) in blood products, we assessed TTI seroprevalence in blood donors and hospitalized patients. METHODS We collected 2760 serum samples from three regions of Hangzhou, Ningbo and Huzhou from April 2021 to March 2022, and they tested by enzyme-linked immunosorbent assay (ELISA) for Hepatitis B surface antigen (HBsAg), Hepatitis C (HCV), Treponema pallidum (TP), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Hepatitis E virus (HEV) and Human T-cell lymphotropic virus type 1/2 (HTLV-1/2) antibody levels. RESULTS Screening test results showed that the positive rates for HBsAg, anti-HCV and anti-TP were 3.01 %, 0.39 % and 0.18 %, respectively. The positive rates for CMV IgM and CMV IgG were 0.76 % and 96.96 %, while the positive rates for EB VCA-IgM and EB EA-IgG were 1.88 % and 10.47 %; those for HEV IgM and HEV IgG were 1.16 % and 26.05 %, while the HTLV-1/2 antibody positive rate was 0.04 %. The positive rates for CMV IgG, EB EA-IgG and HEV IgG in hospitalized patients before transfusion were higher than in volunteer blood donors, and the difference was statistically significant (P < 0.05). The overall co-infection rate was 0.29 %. The positive rates for EB VCA-IgM in the males were significantly higher than in females, and EB VCA-IgM and HEV IgG prevalence varied significantly by age. CONCLUSION Our data demonstrate the risk of TTI exposure and TTI transmission in the Zhejiang population, which poses a threat to blood safety. It is hoped that expansion of pathogen categories (CMV, EBV, HEV and HTLV-1/2) and blood screening programs will contribute to the future adoption of scientific blood transfusion methods.
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Affiliation(s)
- Lin Mengjiao
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xu Yushan
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lv Yan
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Cui Dawei
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | | | - Wang Yongjun
- Key Laboratory of Blood Safety Research of Zhejiang Province, Blood Center of Zhejiang Province, Hangzhou 310052, China
| | - Shen Cuifen
- Department of Clinical Laboratory, Huzhou Central Hospital, Huzhou 313000, China
| | - Xie Jue
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Chen Y, Zhang L, Liu Y, Liu Y, Zhao L, Zhou B, Ruan G, Shi X, Liu X. Clinical features and prognosis of systemic lupus erythematosus complicated by active cytomegalovirus infection: a retrospective cohort study. Front Immunol 2024; 15:1323923. [PMID: 38481991 PMCID: PMC10932949 DOI: 10.3389/fimmu.2024.1323923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/09/2024] [Indexed: 04/06/2024] Open
Abstract
Objective The aim of this study was to investigate the clinical traits and consequences of systemic lupus erythematosus (SLE) complicated by active cytomegalovirus (CMV) infection. Methods This retrospective review involved the examination of medical records for patients diagnosed with SLE who had an active CMV infection at the time of their discharge from Peking Union Medical College Hospital between June 2016 and December 2022. The consistency between plasma CMV deoxyribonucleic acid (DNA) viral load and pp65 antigenemia was analyzed using the chi-square test. Related factors for CMV disease in SLE complicated by active CMV infection patients were analyzed by univariate analysis and multivariable stepwise logistic regression. Cox hazards regression analysis was used to determine predictors for all-cause mortality and CMV recurrence within 3 months. Results A total of 206 patients were enrolled in this study. Of the 123 patients who were detected with both plasma CMV DNA viral load and pp65 antigenemia within an interval not exceeding 72 h, the consistency between plasma CMV DNA viral load and pp65 antigenemia was not good (Kappa = -0.304, p < 0.001). Plasma CMV DNA viral load ≥ 1,600 copies/mL [odds ratio (OR) 4.411, 95% CI 1.871-10.402, p = 0.001], current glucocorticoids dose (equivalent to prednisolone) ≥60 mg/d (OR 2.155, 95% CI 1.071-4.334, p = 0.031), and elevated alanine transaminase (OR 3.409, 95% CI 1.563-7.435, p = 0.002) were significant clinical clues indicating CMV disease in SLE. Multivariable Cox hazards regression analysis showed that CMV organ involvement [hazard ratio (HR) 47.222, 95% CI 5.621-396.689, p < 0.001], SLE multi-system involvement (HR 1.794, 95% CI 1.029-3.128, p = 0.039), and elevated hypersensitive C-reactive protein (hsCRP) (HR 5.767, 95% CI 1.190-27.943, p = 0.030) were independent risk factors for 3-month all-cause mortality. CMV organ involvement (HR 3.404, 95% CI 1.074-10.793, p = 0.037) was an independent risk factor for CMV recurrence within 3 months. Conclusion In SLE patients, plasma CMV DNA viral load seemed to have a higher value in the diagnosis of CMV disease; patients with CMV organ involvement, SLE multi-system involvement, and elevated hsCRP might have a higher risk of 3-month all-cause mortality; and patients with CMV organ involvement might have a higher risk of CMV recurrence within 3 months.
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Affiliation(s)
- Yan Chen
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lifan Zhang
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Epidemiology Unit, Peking Union Medical College, International Clinical Epidemiology Network, Beijing, China
| | - Yuchen Liu
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ye Liu
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Baotong Zhou
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guiren Ruan
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaochun Shi
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaoqing Liu
- Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Clinical Epidemiology Unit, Peking Union Medical College, International Clinical Epidemiology Network, Beijing, China
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35
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Pipitò L, Cascio A. Acute Cytomegalovirus Infection Associated With Erythema Multiforme-Like Eruption: A Case Report. Cureus 2024; 16:e54540. [PMID: 38516453 PMCID: PMC10956636 DOI: 10.7759/cureus.54540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2024] [Indexed: 03/23/2024] Open
Abstract
Human cytomegalovirus infection usually proceeds asymptomatically in immunocompetent patients. In symptomatic forms, mononucleosis syndrome is the most common manifestation. However, atypical cases of cytomegalovirus infections in immunocompetent subjects are reported in the literature. Here, we describe a case of cytomegalovirus-related mononucleosis syndrome that presented with an atypical erythema multiforme-like skin rash and high fever. Very few cases have been described in the literature previously. In our case, the diagnosis was supported by specific serology, and human cytomegalovirus DNA was detected in the blood sample. The clinical picture resolved without the administration of antiviral therapy.
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Affiliation(s)
- Luca Pipitò
- Infectious and Tropical Diseases Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, "G D'Alessandro, University of Palermo, AOUP P. Giaccone, Palermo, ITA
| | - Antonio Cascio
- Infectious and Tropical Diseases Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, "G D'Alessandro, University of Palermo, AOUP P. Giaccone, Palermo, ITA
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36
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Abidi MZ, Schold JD, Kaplan B, Weinberg A, Erlandson KM, Malamon JS. Patient years lost due to cytomegalovirus serostatus mismatching in the scientific registry of transplant recipients. Front Immunol 2024; 14:1292648. [PMID: 38264645 PMCID: PMC10803440 DOI: 10.3389/fimmu.2023.1292648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/21/2023] [Indexed: 01/25/2024] Open
Abstract
Background The cytomegalovirus (CMV) mismatch rate in deceased donor kidney transplant (DDKT) recipients in the US remains above 40%. Since CMV mismatching is common in DDKT recipients, the cumulative effects may be significant in the context of overall patient and graft survival. Our primary objective was to describe the short- and long-term risks associated with high-risk CMV donor positive/recipient negative (D+/R-) mismatching among DDKT recipients with the explicit goal of deriving a mathematical mismatching penalty. Methods We conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients (SRTR) database using donor-matched DDKT recipient pairs (N=105,608) transplanted between 2011-2022. All-cause mortality and graft failure hazard ratios were calculated from one year to ten years post-DDKT. All-cause graft failure included death events. Survival curves were calculated using the Kaplan-Meier estimation at 10 years post-DDKT and extrapolated to 20 years to provide the average graft days lost (aGDL) and average patient days lost (aPDL) due to CMV D+/R- serostatus mismatching. We also performed an age-based stratification analysis to compare the relative risk of CMV D+ mismatching by age. Results Among 31,518 CMV D+/R- recipients, at 1 year post-DDKT, the relative risk of death increased by 29% (p<0.001), and graft failure increased by 17% (p<0.001) as compared to matched CMV D+/R+ group (N=31,518). Age stratification demonstrated a significant increase in the risk associated with CMV mismatching in patients 40 years of age and greater. The aGDL per patient due to mismatching was 125 days and the aPDL per patient was 100 days. Conclusion The risks of CMV D+/R- mismatching are seen both at 1 year post-DDKT period and accumulated throughout the lifespan of the patient, with the average CMV D+/R- recipient losing more than three months of post-DDKT survival time. CMV D+/R- mismatching poses a more significant risk and a greater health burden than previously reported, thus obviating the need for better preventive strategies including CMV serodirected organ allocation to prolong lifespans and graft survival in high-risk patients.
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Affiliation(s)
- Maheen Z. Abidi
- Department of Medicine, Division of Infectious Diseases, University of Colorado, Aurora, CO, United States
| | - Jesse D. Schold
- Department of Surgery, Division of Transplant Surgery, University of Colorado, Aurora, CO, United States
- Colorado Center for Transplantation Care (CCTCARE), Research and Education, Division of Transplant Surgery, Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
| | - Bruce Kaplan
- Department of Surgery, Division of Transplant Surgery, University of Colorado, Aurora, CO, United States
- Colorado Center for Transplantation Care (CCTCARE), Research and Education, Division of Transplant Surgery, Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
| | - Adriana Weinberg
- Department of Medicine, Division of Infectious Diseases, University of Colorado, Aurora, CO, United States
- Department of Pediatrics and Pathology, University of Colorado, Aurora, CO, United States
| | - Kristine M. Erlandson
- Department of Medicine, Division of Infectious Diseases, University of Colorado, Aurora, CO, United States
| | - John S. Malamon
- Department of Surgery, Division of Transplant Surgery, University of Colorado, Aurora, CO, United States
- Colorado Center for Transplantation Care (CCTCARE), Research and Education, Division of Transplant Surgery, Department of Surgery, Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
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Thomas S, Duraisamy SK, Ahmed R, Abraham A, Vishwabandhya A, Mathews V, Srivastava A, Samuel P, Kannangai R, Abraham OC, George B, Abraham AM. Early detection, reactivation of cytomegalovirus DNA & immediate early (IE)-mRNA expression in hematopoietic stem cell-transplant patients. Indian J Med Microbiol 2024; 47:100521. [PMID: 38072066 DOI: 10.1016/j.ijmmb.2023.100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 11/26/2023] [Accepted: 12/04/2023] [Indexed: 12/22/2023]
Abstract
BACKGROUND Human cytomegalovirus (HCMV) reactivation is a major cause of morbidity and mortality among stem cell transplant recipients post-transplantation. AIM HCMV immediate-early messenger RNA (IE-mRNA) was evaluated as marker of post-transplant HCMV reactivation in bone marrow transplant recipients. METHOD ology: An in-house real-time reverse transcriptase PCR targeting IE-mRNA was developed to estimate HCMV mRNA levels post-transplantation. Blood samples collected in K2-EDTA tubes from patients (n = 162) admitted with Department of Clinical Hematology were transported in cold condition for routine HCMV DNA screening. For HCMV IE-mRNA quantification, peripheral blood mononuclear cells (PBMCs) were separated from whole blood and stored in RNA later at -70 °C until testing. Samples were collected weekly once for first 3 weeks post-transplantation and thereafter from week 4-12, samples were collected twice weekly. A total of 2467 samples were collected from 162 study participants. RESULTS Thirty five patients (21.6 %) had post-transplant HCMV reactivation. Twenty five patients with complete follow-up were selected for monitoring HCMV DNA. HCMV IE-mRNA PCR was performed for 15 patients and 7(46.6 %) patients had detectable mRNA levels. HCMV IE-mRNA was detected in all patients with increasing HCMV DNA levels except for one patient in whom IE-mRNA appeared 3 days before HCMV DNA was detected. One patient had detectable HCMV IE-mRNA during declining HCMV DNA level. However the patient showed an increased HCMV DNA one week later, indicating the importance of HCMV mRNA in predicting HCMV replication. CONCLUSION Quantification of HCMV IE-mRNA may be a valuable tool to predict progression of HCMV infection post-transplantation, with further prospective studies needed for validation.
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Affiliation(s)
- Sangeeta Thomas
- Department of Clinical Virology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | | | - Rayaz Ahmed
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Aby Abraham
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Auro Vishwabandhya
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Vikram Mathews
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Alok Srivastava
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Prasanna Samuel
- Department of Biostatistics, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Rajesh Kannangai
- Department of Clinical Virology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - O C Abraham
- Department of Medicine, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Biju George
- Department of Clinical Hematology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
| | - Asha Mary Abraham
- Department of Clinical Virology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
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Schardt JS, Walseng E, Le K, Yang C, Shah P, Fu Y, Alam K, Kelton CR, Gu Y, Huang F, Lin J, Liu W, Dippel A, Zhang H, Mulgrew K, Pryts S, Chennupati V, Chen HC, Denham J, Chen X, Pradhan P, Wu Y, Hardman C, Zhao C, Kierny M, Song Y, Dovedi SJ, Cemerski S, Mazor Y. IL-2-armored peptide-major histocompatibility class I bispecific antibodies redirect antiviral effector memory CD8+ T cells to induce potent anti-cancer cytotoxic activity with limited cytokine release. MAbs 2024; 16:2395499. [PMID: 39205483 PMCID: PMC11364066 DOI: 10.1080/19420862.2024.2395499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/31/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
T cell engagers (TCEs) are becoming an integral class of biological therapeutic owing to their highly potent ability to eradicate cancer cells. Nevertheless, the widespread utility of classical CD3-targeted TCEs has been limited by narrow therapeutic index (TI) linked to systemic CD4+ T cell activation and aberrant cytokine release. One attractive approach to circumvent the systemic activation of pan CD3+ T cells and reduce the risk of cytokine release syndrome is to redirect specific subsets of T cells. A promising strategy is the use of peptide-major histocompatibility class I bispecific antibodies (pMHC-IgGs), which have emerged as an intriguing modality of TCE, based on their ability to selectively redirect highly reactive viral-specific effector memory cytotoxic CD8+ T cells to eliminate cancer cells. However, the relatively low frequency of these effector memory cells in human peripheral blood mononuclear cells (PBMCs) may hamper their redirection as effector cells for clinical applications. To mitigate this potential limitation, we report here the generation of a pMHC-IgG derivative known as guided-pMHC-staging (GPS) carrying a covalent fusion of a monovalent interleukin-2 (IL-2) mutein (H16A, F42A). Using an anti-epidermal growth factor receptor (EGFR) arm as a proof-of-concept, tumor-associated antigen paired with a single-chain HLA-A *02:01/CMVpp65 pMHC fusion moiety, we demonstrate in vitro that the IL-2-armored GPS modality robustly expands CMVpp65-specific CD8+ effector memory T cells and induces potent cytotoxic activity against target cancer cells. Similar to GPS, IL-2-armored GPS molecules induce modulated T cell activation and reduced cytokine release profile compared to an analogous CD3-targeted TCE. In vivo we show that IL-2-armored GPS, but not the corresponding GPS, effectively expands grafted CMVpp65 CD8+ T cells from unstimulated human PBMCs in an NSG mouse model. Lastly, we demonstrate that the IL-2-armored GPS modality exhibits a favorable developability profile and monoclonal antibody-like pharmacokinetic properties in human neonatal Fc receptor transgenic mice. Overall, IL-2-armored GPS represents an attractive approach for treating cancer with the potential for inducing vaccine-like antiviral T cell expansion, immune cell redirection as a TCE, and significantly widened TI due to reduced cytokine release.
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Affiliation(s)
- John S. Schardt
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Even Walseng
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Kim Le
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Chunning Yang
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Pooja Shah
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Ying Fu
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Kausar Alam
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | | | - Yu Gu
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Fengying Huang
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Jia Lin
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Wenhai Liu
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Andrew Dippel
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Hanzhi Zhang
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | | | - Stacy Pryts
- Oncology ICC, AstraZeneca, Gaithersburg, MD, USA
| | | | - Hung-Chang Chen
- Data Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USA
| | | | | | | | - Yuling Wu
- Oncology ICC, AstraZeneca, Cambridge, UK
| | - Colin Hardman
- Discovery Bioanalysis, Clinical Pharmacology & Safety Sciences (CPSS), R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Chihao Zhao
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Michael Kierny
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Yang Song
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
| | - Simon J. Dovedi
- Data Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USA
| | | | - Yariv Mazor
- R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
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Sulaiman NY, Anuar NA, Arshad N, Cheong CS, Liong CC, Khairullah S, Chin EFM, Bee PC, Sam IC, Iyadorai T, Gan GG. CMV Infection Post Allogeneic Hematopoietic Stem Cell Transplantation in a Resource Limited Country. Indian J Hematol Blood Transfus 2024; 40:97-102. [PMID: 38312192 PMCID: PMC10830936 DOI: 10.1007/s12288-023-01655-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/25/2023] [Indexed: 02/06/2024] Open
Abstract
Cytomegalovirus (CMV) infection is one of the common complications which can lead to significant morbidity and mortality in patients after allogeneic hematopoietic stem cell transplantation (HSCT). As the seroprevalence of CMV infection in Malaysia is high, this study aims to determine the prevalence of CMV infection in patients post HSCT and to evaluate the associated risk factors. Patients who underwent allogeneic HSCT in adult ward from 2008 to 2020 at a tertiary teaching hospital in Kuala Lumpur, Malaysia were studied retrospectively. They were followed up for a minimum of 100 days post-HSCT to determine the incidence of CMV infection. CMV infection was defined according to CMV Drug Development Forum 2014. Risk factors such as type of transplant, serostatus of donor and patients, age, gender, race, presence of graft versus host disease (GVHD) and underlying disease were included for analysis. A total of 112 patients were included. Forty (35.7%) patients had CMV infection with median of onset recorded as 40 days (range 13-95 days). Only haplo-identical HSCT and presence of GVHD were identified as significant risk factors. Patients who had CMV infection had a lower median survival time although this was not statistically significant. The CMV infection rate was comparable with previous reports in Asia and as expected, higher than the western countries. Therefore, vigilant monitoring of CMV infection should be implemented especially in patients who had haplo-identical HSCT and acute GVHD.
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Affiliation(s)
- Noor Yuhyi Sulaiman
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Nur Adila Anuar
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Normala Arshad
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Chin Sum Cheong
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Chee Chiat Liong
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Shasha Khairullah
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Edmund Fui Min Chin
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Ping Chong Bee
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - I Ching Sam
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Thevambiga Iyadorai
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Gin Gin Gan
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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40
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Maresca R, Varca S, Di Vincenzo F, Ainora ME, Mignini I, Papa A, Scaldaferri F, Gasbarrini A, Giustiniani MC, Zocco MA, Laterza L. Cytomegalovirus Infection: An Underrated Target in Inflammatory Bowel Disease Treatment. J Clin Med 2023; 13:130. [PMID: 38202138 PMCID: PMC10779749 DOI: 10.3390/jcm13010130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
CMV infection is still a matter of concern in IBD patients, especially regarding the disease's relapse management. Why IBD patients, particularly those affected by ulcerative colitis, are more susceptible to CMV reactivation is not totally explained, although a weakened immune system could be the reason. Various techniques, ranging from serology to histology, can be employed to detect intestinal CMV infection; however, there is currently disagreement in the literature regarding the most effective diagnostic test. Furthermore, CMV involvement in steroid resistance has been broadly discussed, but whether CMV infection is a cause or consequence of the disease severity and, consequently, steroid refractoriness is still debated. Its potential contribution to the lack of response to advanced therapy and small molecules must be more valued and wholly explored. In this review, we look at the actual literature on CMV in IBD patients, and we suggest a pragmatic algorithm for clinical practice management of CMV infection.
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Affiliation(s)
- Rossella Maresca
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Simone Varca
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Federica Di Vincenzo
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Elena Ainora
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
| | - Irene Mignini
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
| | - Alfredo Papa
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Franco Scaldaferri
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Cristina Giustiniani
- Department of Pathology, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy;
| | - Maria Assunta Zocco
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lucrezia Laterza
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy; (R.M.); (S.V.); (F.D.V.); (M.E.A.); (I.M.); (A.P.); (F.S.); (A.G.); (L.L.)
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Rinaldi I, Muthalib A, Sutandar JW, Kuncoro HA, Harsono BI, Susanto N, Setiawan T, Winston K, Dewantara IR, Amin IF, Shufiyani YM. Cytomegalovirus Infection in Patient with Clear Cell Renal Cell Carcinoma. Case Rep Med 2023; 2023:5560673. [PMID: 38023618 PMCID: PMC10661874 DOI: 10.1155/2023/5560673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 08/08/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Cytomegalovirus (CMV) infection is a widespread condition that can affect individuals of all ages. Most cases of CMV infection are mild and resolve on their own. However, in immunocompromised individuals, such as post-transplant patients or those with cancer, severe infections can occur. While there have been several studies on CMV infection in post-transplant patients, there is limited literature on CMV infection in cancer, particularly in kidney cancer. Case Report. In this case report, we present the case of a 61-year-old man with clear cell renal cell carcinoma who underwent targeted therapy with the receptor tyrosine kinase (RTK) inhibitor lenvatinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus. The patient was hospitalized for 26 days and admitted to the intensive care unit (ICU) due to shortness of breath, decreased oxygen saturation, and irregular breathing. Cytomegalovirus polymerase chain reaction (PCR) test results were positive. Given the high prevalence of CMV infection in developing countries, it is likely that the patient had a reactivation of CMV. As such, the patient was subsequently treated with ganciclovir for 14 days and showed improvement in symptoms such as shortness of breath, cough, fever, and increased oxygen saturation. Following recovery, the patient received maintenance therapy with oral valganciclovir for 7 days. No further symptoms appeared during subsequent cancer treatments. Conclusion Cancer patients who are undergoing treatment are at a higher risk for developing opportunistic infections, which can result in morbidity and mortality. Therefore, healthcare professionals should be aware of the possibility of CMV infection in cancer patients and be prepared to diagnose and treat the infection, particularly in areas where the prevalence of CMV infection is high.
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Affiliation(s)
- Ikhwan Rinaldi
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Abdul Muthalib
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Cipto Mangunkusumo National General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | | | | | | | - Nelly Susanto
- Department of Radiology, Gading Pluit Hospital, Jakarta, Indonesia
| | - Tjondro Setiawan
- Department of Radiology, Gading Pluit Hospital, Jakarta, Indonesia
| | - Kevin Winston
- Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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Boppana SB, van Boven M, Britt WJ, Gantt S, Griffiths PD, Grosse SD, Hyde TB, Lanzieri TM, Mussi-Pinhata MM, Pallas SE, Pinninti SG, Rawlinson WD, Ross SA, Vossen ACTM, Fowler KB. Vaccine value profile for cytomegalovirus. Vaccine 2023; 41 Suppl 2:S53-S75. [PMID: 37806805 DOI: 10.1016/j.vaccine.2023.06.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 04/28/2023] [Accepted: 06/02/2023] [Indexed: 10/10/2023]
Abstract
Cytomegalovirus (CMV) is the most common infectious cause of congenital malformation and a leading cause of developmental disabilities such as sensorineural hearing loss (SNHL), motor and cognitive deficits. The significant disease burden from congenital CMV infection (cCMV) led the US National Institute of Medicine to rank CMV vaccine development as the highest priority. An average of 6.7/1000 live births are affected by cCMV, but the prevalence varies across and within countries. In contrast to other congenital infections such as rubella and toxoplasmosis, the prevalence of cCMV increases with CMV seroprevalence rates in the population. The true global burden of cCMV disease is likely underestimated because most infected infants (85-90 %) have asymptomatic infection and are not identified. However, about 7-11 % of those with asymptomatic infection will develop SNHL throughout early childhood. Although no licensed CMV vaccine exists, several candidate vaccines are in development, including one currently in phase 3 trials. Licensure of one or more vaccine candidates is feasible within the next five years. Various models of CMV vaccine strategies employing different target populations have shown to provide substantial benefit in reducing cCMV. Although CMV can cause end-organ disease with significant morbidity and mortality in immunocompromised individuals, the focus of this vaccine value profile (VVP) is on preventing or reducing the cCMV disease burden. This CMV VVP provides a high-level, comprehensive assessment of the currently available data to inform the potential public health, economic, and societal value of CMV vaccines. The CMV VVP was developed by a working group of subject matter experts from academia, public health groups, policy organizations, and non-profit organizations. All contributors have extensive expertise on various elements of the CMV VVP and have described the state of knowledge and identified the current gaps. The VVP was developed using only existing and publicly available information.
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Affiliation(s)
- Suresh B Boppana
- Departments of Pediatrics and Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Michiel van Boven
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, and Julius Center for Health Sciences and Primary Care, Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - William J Britt
- Departments of Pediatrics, Microbiology, and Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, USA
| | - Soren Gantt
- Centre de recherche du CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada
| | - Paul D Griffiths
- Emeritus Professor of Virology, University College London, United Kingdom
| | - Scott D Grosse
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
| | - Terri B Hyde
- Global Immunization Division, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Tatiana M Lanzieri
- Measles, Rubella, and Cytomegalovirus Epidemiology Team, Viral Vaccine Preventable Diseases Branch / Division of Viral Diseases. National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Marisa M Mussi-Pinhata
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Brazil
| | - Sarah E Pallas
- Global Immunization Division, Center for Global Health, U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329-4027, USA
| | - Swetha G Pinninti
- Departments of Pediatrics and Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - William D Rawlinson
- Serology and Virology Division, NSW Health Pathology Randwick, Prince of Wales Hospital, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, and School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Shannon A Ross
- Departments of Pediatrics and Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ann C T M Vossen
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Karen B Fowler
- Departments of Pediatrics and Epidemiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
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Streck NT, Espy MJ, Ferber MJ, Klee EW, Razonable RR, Gonzalez D, Sayada C, Heaton PR, Chou S, Binnicker MJ. Use of next-generation sequencing to detect mutations associated with antiviral drug resistance in cytomegalovirus. J Clin Microbiol 2023; 61:e0042923. [PMID: 37750719 PMCID: PMC10595055 DOI: 10.1128/jcm.00429-23] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/25/2023] [Indexed: 09/27/2023] Open
Abstract
Cytomegalovirus (CMV) is a significant cause of morbidity and mortality among immunocompromised hosts, including transplant recipients. Antiviral prophylaxis or treatment is used to reduce the incidence of CMV disease in this patient population; however, there is concern about increasing antiviral resistance. Detection of antiviral resistance in CMV was traditionally accomplished using Sanger sequencing of UL54 and UL97 genes, in which specific mutations may result in reduced antiviral activity. In this study, a novel next-generation sequencing (NGS) method was developed and validated to detect mutations in UL54/UL97 associated with antiviral resistance. Plasma samples (n = 27) submitted for antiviral resistance testing by Sanger sequencing were also analyzed using the NGS method. When compared to Sanger sequencing, the NGS assay demonstrated 100% (27/27) overall agreement for determining antiviral resistance/susceptibility and 88% (22/25) agreement at the level of resistance-associated mutations. The limit of detection of the NGS method was determined to be 500 IU/mL, and the lower threshold for detecting mutations associated with resistance was established at 15%. The NGS assay represents a novel laboratory tool that assists healthcare providers in treating patients who are infected with CMV harboring resistance-associated mutations and who may benefit from tailored antiviral therapy.
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Affiliation(s)
- Nicholas T. Streck
- Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark J. Espy
- Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew J. Ferber
- Division of Laboratory Genetics and Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Eric W. Klee
- Division of Biomedical Statistics and Informatics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Raymund R. Razonable
- Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Phillip R. Heaton
- Health Partners Medical Laboratory and Pathology Services, Bloomington, Minnesota, USA
| | - Sunwen Chou
- Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon, USA
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44
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Zwezdaryk KJ, Kaur A. Role of immunometabolism during congenital cytomegalovirus infection. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00034. [PMID: 38037590 PMCID: PMC10683969 DOI: 10.1097/in9.0000000000000034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023]
Abstract
Cytomegalovirus (CMV) is a master manipulator of host metabolic pathways. The impact of CMV metabolic rewiring during congenital CMV on immune function is unknown. CMV infection can directly alter glycolytic and oxidative phosphorylation pathways in infected cells. Recent data suggests CMV may alter metabolism in uninfected neighboring cells. In this mini review, we discuss how CMV infection may impact immune function through metabolic pathways. We discuss how immune cells differ between maternal and decidual compartments and how altered immunometabolism may contribute to congenital infections.
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Affiliation(s)
- Kevin J. Zwezdaryk
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA
- Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA, USA
- Tulane Brain Institute, Tulane University School of Medicine, New Orleans, LA, USA
| | - Amitinder Kaur
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, USA
- Division of Immunology, Tulane National Primate Research Center, Covington, LA, USA
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45
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Kang KW, Jeon MJ, Yu ES, Kim DS, Lee BH, Lee SR, Choi CW, Park Y, Kim BS, Sung HJ. Cytomegalovirus reactivation under pre-emptive therapy following allogeneic hematopoietic stem cell transplant: Pattern, survival, and risk factors in the Republic of Korea. PLoS One 2023; 18:e0291268. [PMID: 37703263 PMCID: PMC10499250 DOI: 10.1371/journal.pone.0291268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 08/24/2023] [Indexed: 09/15/2023] Open
Abstract
INTRODUCTION Pre-emptive therapy for cytomegalovirus (CMV) reactivation has been used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear if this strategy has poorer clinical outcomes in CMV-endemic areas and if more aggressive prophylaxis is required. METHODS We retrospectively analyzed the patterns and survival after CMV reactivation in patients undergoing pre-emptive therapy following allo-HSCT and assessed high-risk patients who could benefit from aggressive CMV prophylaxis in endemic areas. RESULTS Of the 292 patients who underwent allo-HSCT, 70.5% (donor+ or recipient+) were CMV seropositive. CMV reactivation occurred in 139 patients (47.6%), with a median of 31.5 days from day 0 of allo-HSCT. The overall survival of patients with CMV reactivation who received pre-emptive therapy did not differ from those without reactivation. Of the 139 patients with CMV reactivation, 78 (56.1%) underwent ≥2 rounds of pre-emptive therapy. In multivariate analysis, the risk of CMV reactivation was higher in patients with multiple myeloma, with CMV seropositivity of the recipient and donor, administered with a higher dose of anti-thymocyte globulin (ATG), and with acute graft-versus-host disease (aGVHD) ≥ grade 2. CONCLUSION Although half of the patients with allo-HSCT were administered with pre-emptive therapy for CMV, CMV reactivation did not affect their survival, indicating the advantages of pre-emptive therapy, even in CMV-endemic areas. The cost-effectiveness of more aggressive CMV prophylaxis should be re-evaluated in patients at a high risk for CMV reactivation.
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Affiliation(s)
- Ka-Won Kang
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Min Ji Jeon
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Eun Sang Yu
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Dae Sik Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Byung-Hyun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Se Ryeon Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Chul Won Choi
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yong Park
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Byung Soo Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hwa Jung Sung
- Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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46
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Dremel SE, Tagawa T, Koparde VN, Arbuckle JH, Kristie TM, Krug LT, Ziegelbauer JM. Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.07.556698. [PMID: 37886542 PMCID: PMC10602050 DOI: 10.1101/2023.09.07.556698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
A first line of defense during infection is expression of interferon (IFN)-stimulated gene products which suppress viral lytic infection. To combat this, herpesviruses express endoribonucleases to deplete host RNAs. Here we demonstrate that IFN-induced circular RNAs (circRNAs) can escape viral-mediated degradation. We performed comparative circRNA expression profiling for representative alpha- (Herpes simplex virus-1, HSV-1), beta- (human cytomegalovirus, HCMV), and gamma-herpesviruses (Kaposi sarcoma herpesvirus, KSHV; murine gamma-herpesvirus 68, MHV68). Strikingly, we found that circRNAs are, as a population, resistant to host shutoff. This observation was confirmed by ectopic expression assays of human and murine herpesvirus endoribonucleases. During primary lytic infection, ten circRNAs were commonly regulated across all subfamilies of human herpesviruses, suggesting a common mechanism of regulation. We tested one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs were upregulated by either IFN-β or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we found an interferon-stimulated circRNA, circRELL1, inhibited lytic HSV-1 infection. We have previously reported circRELL1 inhibits lytic KSHV infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape.
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Affiliation(s)
- Sarah E. Dremel
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, United States
| | - Takanobu Tagawa
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, United States
| | - Vishal N. Koparde
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- Advanced Biomedical Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, United States
| | - Jesse H. Arbuckle
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
| | - Thomas M. Kristie
- Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
| | - Laurie T. Krug
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, United States
| | - Joseph M. Ziegelbauer
- HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, United States
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47
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Herman JD, Atyeo C, Zur Y, Cook CE, Patel NJ, Vanni KM, Kowalski EN, Qian G, Srivatsan S, Shadick NA, Rao DA, Kellman B, Mann CJ, Lauffenburger D, Wallace ZS, Sparks JA, Alter G. Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases. Sci Transl Med 2023; 15:eadf6598. [PMID: 37672567 PMCID: PMC10764151 DOI: 10.1126/scitranslmed.adf6598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 08/05/2023] [Indexed: 09/08/2023]
Abstract
Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2- or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti-SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs.
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Affiliation(s)
- Jonathan D Herman
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
- Division of Infectious Disease, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Caroline Atyeo
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Yonatan Zur
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Claire E Cook
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Naomi J Patel
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kathleen M Vanni
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Emily N Kowalski
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Grace Qian
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Shruthi Srivatsan
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Nancy A Shadick
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Deepak A Rao
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Benjamin Kellman
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Colin J Mann
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Douglas Lauffenburger
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Zachary S Wallace
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Jeffrey A Sparks
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Galit Alter
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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48
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Wang D, Chen YH, Ventresca M. Optimizing age specific strategies of vaccination for prevention of cytomegalovirus infection in the US using agent-based simulation. Epidemics 2023; 44:100698. [PMID: 37354657 DOI: 10.1016/j.epidem.2023.100698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 06/03/2023] [Accepted: 06/12/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND There is an urgent need to develop a cytomegalovirus (CMV) vaccine as it remains the leading cause of birth defects in the United States. While several CMV vaccine candidates are currently in late-stage clinical trials, the most effective vaccination program remains an open research question. METHODS To take into account the critical uncertainties when evaluating the vaccine impact on both vertical (congenital) and horizontal CMV transmissions, we developed a CMV agent-based model representative of the US population and contact network structures. RESULTS We evaluated 648 vaccination scenarios under various assumptions of vaccination age, vaccine efficacy, protection duration, and vaccination coverage. The optimal age of vaccination under all scenarios is shown to be during early childhood. However, a relatively modest benefit was also seen with vaccination of females of reproduction age (around age of 25) assuming near universal coverage and long vaccine-mediated protection. CONCLUSIONS This study highlights the important need for a pediatric vaccination program in mitigating CMV in the United States. Our model is poised to investigate further location-based vaccine effectiveness questions in future planning of both clinical trials as well as eventual program implementation.
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Affiliation(s)
- Dawei Wang
- Health Economic and Decision Sciences, Merck & Co., Inc., Kenilworth, NJ, USA.
| | - Yao-Hsuan Chen
- Health Economic and Decision Sciences, MSD, Kings Cross, London, UK
| | - Mario Ventresca
- School of Industrial Engineering, Purdue University, 315 Grant St, West Lafayette, IN 47906, USA
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49
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Wunderlich W, Sidebottom AC, Schulte AK, Taghon J, Dollard S, Hernandez-Alvarado N. The Use of Saliva Samples to Test for Congenital Cytomegalovirus Infection in Newborns: Examination of False-Positive Samples Associated with Donor Milk Use. Int J Neonatal Screen 2023; 9:46. [PMID: 37606483 PMCID: PMC10443263 DOI: 10.3390/ijns9030046] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/20/2023] [Accepted: 08/09/2023] [Indexed: 08/23/2023] Open
Abstract
A universal screening research study was conducted in six hospitals to identify the clinical sensitivity of polymerase chain reaction (PCR) testing on newborn dried blood spots (DBSs) versus saliva specimens for the diagnosis of congenital cytomegalovirus (cCMV). CMV DNA positive results from DBSs or saliva were confirmed with urine testing. Findings of several false-positive (FP) saliva PCR results prompted an examination of a possible association with donor milk. Documentation of the frequency of positive saliva results, including both true-positive (TP) and FP status from clinical confirmation, occurred. The frequency of donor milk use was compared for TP and FP cases. Of 22,079 participants tested between 2016 and 2022, 96 had positive saliva results, 15 were determined to be FP, 79 TP, and 2 were excluded for incomplete clinical evaluation. Newborn donor milk use was identified for 18 (19.14%) of all the positive saliva screens. Among the 15 FPs, 11 (73.33%) consumed donor milk compared to 7 of the 79 TPs (8.8%) (OR 28.29, 95% CI 7.10-112.73, p < 0.001). While milk bank Holder pasteurization inactivates CMV infectivity, CMV DNA may still be detectable. Due to this possible association, screening programs that undertake testing saliva for CMV DNA may benefit from documenting donor milk use as a potential increased risk for FP results.
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Affiliation(s)
- Whitney Wunderlich
- Care Delivery Research, Allina Health, Minneapolis, MN 55410, USA; (A.C.S.); (A.K.S.); (J.T.)
| | - Abbey C. Sidebottom
- Care Delivery Research, Allina Health, Minneapolis, MN 55410, USA; (A.C.S.); (A.K.S.); (J.T.)
| | - Anna K. Schulte
- Care Delivery Research, Allina Health, Minneapolis, MN 55410, USA; (A.C.S.); (A.K.S.); (J.T.)
| | - Jessica Taghon
- Care Delivery Research, Allina Health, Minneapolis, MN 55410, USA; (A.C.S.); (A.K.S.); (J.T.)
| | - Sheila Dollard
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA;
| | - Nelmary Hernandez-Alvarado
- Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA;
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50
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Bergkamp ND, van Senten JR, Brink HJ, Bebelman MP, van den Bor J, Çobanoğlu TS, Dinkla K, Köster J, Klau G, Siderius M, Smit MJ. A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P 1 signaling axis. Sci Signal 2023; 16:eade6737. [PMID: 37582160 DOI: 10.1126/scisignal.ade6737] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 07/27/2023] [Indexed: 08/17/2023]
Abstract
The G protein-coupled receptor (GPCR) US28 encoded by the human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas, aggressive brain tumors with a generally poor prognosis. Here, we showed that US28 increased the malignancy of U251 glioblastoma cells by enhancing signaling mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that stimulates oncogenic pathways in glioblastoma. US28 expression increased the abundance of the key components of the S1P signaling axis, including an enzyme that generates S1P [sphingosine kinase 1 (SK1)], an S1P receptor [S1P receptor 1 (S1P1)], and S1P itself. Enhanced S1P signaling promoted glioblastoma cell proliferation and survival by activating the kinases AKT and CHK1 and the transcriptional regulators cMYC and STAT3 and by increasing the abundance of cancerous inhibitor of PP2A (CIP2A), driving several feed-forward signaling loops. Inhibition of S1P signaling abrogated the proliferative and anti-apoptotic effects of US28. US28 also activated the S1P signaling axis in HCMV-infected cells. This study uncovers central roles for S1P and CIP2A in feed-forward signaling that contributes to the US28-mediated exacerbation of glioblastoma.
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Affiliation(s)
- Nick D Bergkamp
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jeffrey R van Senten
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Hendrik J Brink
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Maarten P Bebelman
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jelle van den Bor
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Tuğçe S Çobanoğlu
- Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | | | - Johannes Köster
- Algorithms for Reproducible Bioinformatics, Institute of Human Genetics, Faculty of Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Medical Oncology, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Gunnar Klau
- Algorithmic Bioinformatics, Department of Computer Science, Heinrich Heine University, Düsseldorf, Germany
| | - Marco Siderius
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Martine J Smit
- Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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