1
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Rong Z, Mai H, Ebert G, Kapoor S, Puelles VG, Czogalla J, Hu S, Su J, Prtvar D, Singh I, Schädler J, Delbridge C, Steinke H, Frenzel H, Schmidt K, Braun C, Bruch G, Ruf V, Ali M, Sühs KW, Nemati M, Hopfner F, Ulukaya S, Jeridi D, Mistretta D, Caliskan ÖS, Wettengel JM, Cherif F, Kolabas ZI, Molbay M, Horvath I, Zhao S, Krahmer N, Yildirim AÖ, Ussar S, Herms J, Huber TB, Tahirovic S, Schwarzmaier SM, Plesnila N, Höglinger G, Ondruschka B, Bechmann I, Protzer U, Elsner M, Bhatia HS, Hellal F, Ertürk A. Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. Cell Host Microbe 2024; 32:2112-2130.e10. [PMID: 39615487 DOI: 10.1016/j.chom.2024.11.007] [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: 08/26/2024] [Revised: 10/10/2024] [Accepted: 11/08/2024] [Indexed: 12/14/2024]
Abstract
SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.
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Affiliation(s)
- Zhouyi Rong
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Medical Research School (MMRS), Munich, Germany
| | - Hongcheng Mai
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Munich Medical Research School (MMRS), Munich, Germany
| | - Gregor Ebert
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Saketh Kapoor
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Victor G Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Jan Czogalla
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Senbin Hu
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jinpeng Su
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | - Danilo Prtvar
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Inderjeet Singh
- Research Unit Adipocytes & Metabolism (ADM), Helmholtz Diabetes Center, Helmholtz Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Julia Schädler
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claire Delbridge
- Institute of Pathology, Division of Neuropathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hanno Steinke
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Hannah Frenzel
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Katja Schmidt
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Christian Braun
- Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Gina Bruch
- Institute of Legal Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Viktoria Ruf
- Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Mayar Ali
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Graduate School of Neuroscience (GSN), Munich, Germany
| | | | - Mojtaba Nemati
- Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Franziska Hopfner
- Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Selin Ulukaya
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany
| | - Denise Jeridi
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany
| | - Daniele Mistretta
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany
| | | | | | - Fatma Cherif
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Zeynep Ilgin Kolabas
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Graduate School of Neuroscience (GSN), Munich, Germany
| | - Müge Molbay
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Medical Research School (MMRS), Munich, Germany
| | - Izabela Horvath
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Center of Doctoral Studies in Informatics and its Applications (CEDOSIA), Technical University of Munich, Munich, Germany
| | - Shan Zhao
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Natalie Krahmer
- Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany
| | - Ali Önder Yildirim
- Institute of Lung Health and Immunity (LHI), Comprehensive Pneumology Center (CPC), Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Siegfried Ussar
- Research Unit Adipocytes & Metabolism (ADM), Helmholtz Diabetes Center, Helmholtz Munich, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Jochen Herms
- Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabina Tahirovic
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Susanne M Schwarzmaier
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Nikolaus Plesnila
- Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Günter Höglinger
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Department of Neurology, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Benjamin Ondruschka
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ingo Bechmann
- Institute of Anatomy, University of Leipzig, Leipzig, Germany
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Munich, Munich, Germany; German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
| | - Markus Elsner
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany
| | - Harsharan Singh Bhatia
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Farida Hellal
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Ali Ertürk
- Institute for Tissue Engineering and Regenerative Medicine (iTERM), Helmholtz Munich, Neuherberg, Germany; Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Koç University, School of Medicine, İstanbul, Turkey.
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Dos Reis RS, Selvam S, Ayyavoo V. Neuroinflammation in Post COVID-19 Sequelae: Neuroinvasion and Neuroimmune Crosstalk. Rev Med Virol 2024; 34:e70009. [PMID: 39558491 DOI: 10.1002/rmv.70009] [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: 06/04/2024] [Revised: 10/24/2024] [Accepted: 11/03/2024] [Indexed: 11/20/2024]
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 triggered a swift global spread, leading to a devastating pandemic. Alarmingly, approximately one in four individuals diagnosed with coronavirus disease 2019 (COVID-19) experience varying degrees of cognitive impairment, raising concerns about a potential increase in neurological sequelae cases. Neuroinflammation seems to be the key pathophysiological hallmark linking mild respiratory COVID-19 to cognitive impairment, fatigue, and neurological sequelae in COVID-19 patients, highlighting the interaction between the nervous and immune systems following SARS-CoV-2 infection. Several hypotheses have been proposed to explain how the virus disrupts physiological pathways to trigger inflammation within the CNS, potentially leading to neuronal damage. These include neuroinvasion, systemic inflammation, disruption of the lung and gut-brain axes, and reactivation of latent viruses. This review explores the potential origins of neuroinflammation and the underlying neuroimmune cross-talk, highlighting important unanswered questions in the field. Addressing these fundamental issues could enhance our understanding of the virus's impact on the CNS and inform strategies to mitigate its detrimental effects.
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Affiliation(s)
- Roberta S Dos Reis
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sathish Selvam
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Velpandi Ayyavoo
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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3
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Lin J, Zheng D, Tian D, Zheng P, Zhang H, Li C, Lei C, Shi F, Wang H. High Frequency of Autoantibodies in COVID-19 Patients with Central Nervous System Complications: a Multicenter Observational Study. Mol Neurobiol 2024; 61:8414-8424. [PMID: 38507030 DOI: 10.1007/s12035-024-04109-4] [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: 12/25/2023] [Accepted: 03/08/2024] [Indexed: 03/22/2024]
Abstract
We present a panel of central nervous system (CNS) complications associated with coronavirus disease 2019 (COVID-19) and their clinical characteristics. We aim to investigate associations between neurological autoantibodies and COVID-19 patients with predominant CNS complications. In this retrospective multi-center study, we analyze neurologic complications associated with COVID-19 patients from Dec. 2022 to Feb. 2023 at four tertiary hospitals in China. CSF and/or serum in the enrolled patients were tested for autoantibodies using tissue-based assays (TBAs) and cell-based assays (CBAs). A total of 34 consecutive patients (median age was 40.5 years [range 15-83], 50% were female) were enrolled. CNS syndromes included encephalitis (n=15), encephalopathies (n=6), meningoencephalitis (n=3), ADEM (n=2), depression (n = 2), Alzheimer's disease (n=2), Parkinson disease (n=1), and central nervous system vasculitis (n=1). Twenty-eight specimens (of 44 tested; 11/27 [40.7%] CSF, 13/17 [76.5%] serums) were confirmed by TBAs to be autoantibodies positive. However, only a few autoantibodies (1 with MOG and 1 with NMDAR) were detected by CBAs assays. Twenty-four patients received immunotherapy. After a mean time of 7.26 months of follow-up, 75.8% (25/33) of patients had good outcome (mRS score ≤2). Although no significant difference was observed between the two groups, the proportion of positive CSF autoantibodies in the poor outcomes group was higher than that in the good outcomes group (57.1% vs 31.5%, P = 0.369). Autoantibodies were frequently observed in COVID-19-associated CNS complications. The identification of these autoantibody-positive COVID-19 cases is important as they respond favorably to immunotherapy.
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Affiliation(s)
- Jingfang Lin
- Department of Neurology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Dong Zheng
- Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Decai Tian
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Pei Zheng
- Center for Neurological Diseases, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Hongya Zhang
- Department of Neurology, Shenzhen University General Hospital, Shenzhen, China
| | - Chuo Li
- Department of Neurology, Eight People's Hospital of Guangzhou, Guangzhou, China
| | - Chunliang Lei
- Eight People's Hospital of Guangzhou, Guangzhou, China
| | - Fudong Shi
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Center for Neurological Diseases, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Honghao Wang
- Department of Neurology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
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4
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Hao M, He Y, Song T, Guo H, Rayman MP, Zhang J. Dopamine and its precursor levodopa inactivate SARS-CoV-2 main protease by forming a quinoprotein. Free Radic Biol Med 2024; 220:167-178. [PMID: 38718952 DOI: 10.1016/j.freeradbiomed.2024.05.008] [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] [Received: 03/12/2024] [Revised: 04/10/2024] [Accepted: 05/04/2024] [Indexed: 05/12/2024]
Abstract
Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa-o-quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor.
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Affiliation(s)
- Meng Hao
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Anhui Agricultural University, Hefei, 230036, China
| | - Yufeng He
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Anhui Agricultural University, Hefei, 230036, China
| | - Tingting Song
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Anhui Agricultural University, Hefei, 230036, China
| | - Huimin Guo
- Center for Biological Technology, Anhui Agricultural University, Hefei, 230036, China
| | - Margaret P Rayman
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7XH, UK
| | - Jinsong Zhang
- State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Anhui Agricultural University, Hefei, 230036, China.
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Vashisht A, Vashisht V, Singh H, Ahluwalia P, Mondal AK, Williams C, Farmaha J, Woodall J, Kolhe R. Neurological Complications of COVID-19: Unraveling the Pathophysiological Underpinnings and Therapeutic Implications. Viruses 2024; 16:1183. [PMID: 39205157 PMCID: PMC11359204 DOI: 10.3390/v16081183] [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: 06/11/2024] [Revised: 07/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), induced a global pandemic with a diverse array of clinical manifestations. While the acute phase of the pandemic may be waning, the intricacies of COVID-19's impact on neurological health remain a crucial area of investigation. Early recognition of the spectrum of COVID-19 symptoms, ranging from mild fever and cough to life-threatening respiratory distress and multi-organ failure, underscored the significance of neurological complications, including anosmia, seizures, stroke, disorientation, encephalopathy, and paralysis. Notably, patients requiring intensive care unit (ICU) admission due to neurological challenges or due to them exhibiting neurological abnormalities in the ICU have shown increased mortality rates. COVID-19 can lead to a range of neurological complications such as anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, seizures, etc., in affected patients. This review elucidates the burgeoning landscape of neurological sequelae associated with SARS-CoV-2 infection and explores the underlying neurobiological mechanisms driving these diverse manifestations. A meticulous examination of potential neuroinvasion routes by SARS-CoV-2 underscores the intricate interplay between the virus and the nervous system. Moreover, we dissect the diverse neurological manifestations emphasizing the necessity of a multifaceted approach to understanding the disease's neurological footprint. In addition to elucidating the pathophysiological underpinnings, this review surveys current therapeutic modalities and delineates prospective avenues for neuro-COVID research. By integrating epidemiological, clinical, and diagnostic parameters, we endeavor to foster a comprehensive analysis of the nexus between COVID-19 and neurological health, thereby laying the groundwork for targeted therapeutic interventions and long-term management strategies.
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Affiliation(s)
- Ashutosh Vashisht
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Vishakha Vashisht
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Harmanpreet Singh
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Pankaj Ahluwalia
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Ashis K. Mondal
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Colin Williams
- Lincoln Memorial DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN 37902, USA;
| | - Jaspreet Farmaha
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Jana Woodall
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (A.V.); (V.V.); (H.S.); (P.A.); (A.K.M.); (J.F.); (J.W.)
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Krishna VD, Chang A, Korthas H, Var SR, Seelig DM, Low WC, Li L, Cheeran MCJ. Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model. Front Microbiol 2024; 15:1404312. [PMID: 39077737 PMCID: PMC11284165 DOI: 10.3389/fmicb.2024.1404312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/24/2024] [Indexed: 07/31/2024] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice. Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions. These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.
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Affiliation(s)
- Venkatramana D. Krishna
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States
| | - Allison Chang
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | - Holly Korthas
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States
| | - Susanna R. Var
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Davis M. Seelig
- Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Walter C. Low
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Ling Li
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, United States
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States
| | - Maxim C. -J. Cheeran
- Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States
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7
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VanElzakker MB, Bues HF, Brusaferri L, Kim M, Saadi D, Ratai EM, Dougherty DD, Loggia ML. Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [ 11C]PBR28 PET correlates with vascular disease measures. Brain Behav Immun 2024; 119:713-723. [PMID: 38642615 PMCID: PMC11225883 DOI: 10.1016/j.bbi.2024.04.015] [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: 11/01/2023] [Revised: 02/28/2024] [Accepted: 04/16/2024] [Indexed: 04/22/2024] Open
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.
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Affiliation(s)
- Michael B VanElzakker
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; PolyBio Research Foundation, Medford, MA, USA.
| | - Hannah F Bues
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ludovica Brusaferri
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Computer Science And Informatics, School of Engineering, London South Bank University, London, UK
| | - Minhae Kim
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Deena Saadi
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Eva-Maria Ratai
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Darin D Dougherty
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Marco L Loggia
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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8
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Sánchez-Morales L, Porras N, García-Seco T, Pérez-Sancho M, Cruz F, Chinchilla B, Barroso-Arévalo S, Diaz-Frutos M, Buendía A, Moreno I, Briones V, Risalde MDLÁ, de la Fuente J, Juste R, Garrido J, Balseiro A, Gortázar C, Rodríguez-Bertos A, Domínguez M, Domínguez L. Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2. Vet Res 2024; 55:71. [PMID: 38822398 PMCID: PMC11143641 DOI: 10.1186/s13567-024-01325-7] [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: 11/17/2023] [Accepted: 04/27/2024] [Indexed: 06/03/2024] Open
Abstract
In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Guérin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated k18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3-4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3-4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-α and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3-4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although k18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.
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Affiliation(s)
- Lidia Sánchez-Morales
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - Néstor Porras
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
| | - Teresa García-Seco
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
| | - Marta Pérez-Sancho
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain.
| | - Fátima Cruz
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
| | - Blanca Chinchilla
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Production, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - Sandra Barroso-Arévalo
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - Marta Diaz-Frutos
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - Aránzazu Buendía
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
| | - Inmaculada Moreno
- Unidad de Inmunología Microbiana, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Pozuelo-Majadahonda km 2, Majadahonda, 28220, Madrid, Spain
| | - Víctor Briones
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - María de Los Ángeles Risalde
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes (ENZOEM), Universidad de Córdoba, Córdoba, Spain
| | - José de la Fuente
- SaBio Instituto de Investigación en Recursos Cinegéticos, Ciudad Real, Spain
- Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Ramón Juste
- Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
| | - Joseba Garrido
- Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain
| | - Ana Balseiro
- Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de León, 24071, León, Spain
| | - Christian Gortázar
- SaBio Instituto de Investigación en Recursos Cinegéticos, Ciudad Real, Spain
| | - Antonio Rodríguez-Bertos
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Internal Medicine and Animal Surgery, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
| | - Mercedes Domínguez
- Unidad de Inmunología Microbiana, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Carretera Pozuelo-Majadahonda km 2, Majadahonda, 28220, Madrid, Spain
| | - Lucas Domínguez
- VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain
- Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040, Madrid, Spain
- Real Academia de Doctores de España, C. de San Bernardo, 49, 28015, Madrid, Spain
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9
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Dell’Aquila M, Cafiero C, Micera A, Stigliano E, Ottaiano MP, Benincasa G, Schiavone B, Guidobaldi L, Santacroce L, Pisconti S, Arena V, Palmirotta R. SARS-CoV-2-Related Olfactory Dysfunction: Autopsy Findings, Histopathology, and Evaluation of Viral RNA and ACE2 Expression in Olfactory Bulbs. Biomedicines 2024; 12:830. [PMID: 38672185 PMCID: PMC11048640 DOI: 10.3390/biomedicines12040830] [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: 03/07/2024] [Revised: 03/29/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The COVID-19 pandemic has been a health emergency with a significant impact on the world due to its high infectiousness. The disease, primarily identified in the lower respiratory tract, develops with numerous clinical symptoms affecting multiple organs and displays a clinical finding of anosmia. Several authors have investigated the pathogenetic mechanisms of the olfactory disturbances caused by SARS-CoV-2 infection, proposing different hypotheses and showing contradictory results. Since uncertainties remain about possible virus neurotropism and direct damage to the olfactory bulb, we investigated the expression of SARS-CoV-2 as well as ACE2 receptor transcripts in autoptic lung and olfactory bulb tissues, with respect to the histopathological features. METHODS Twenty-five COVID-19 olfactory bulbs and lung tissues were randomly collected from 200 initial autopsies performed during the COVID-19 pandemic. Routine diagnosis was based on clinical and radiological findings and were confirmed with post-mortem swabs. Real-time RT-PCR for SARS-CoV-2 and ACE2 receptor RNA was carried out on autoptic FFPE lung and olfactory bulb tissues. Histological staining was performed on tissue specimens and compared with the molecular data. RESULTS While real-time RT-PCR for SARS-CoV-2 was positive in 23 out of 25 lung samples, the viral RNA expression was absent in olfactory bulbs. ACE2-receptor RNA was present in all tissues examined, being highly expressed in lung samples than olfactory bulbs. CONCLUSIONS Our finding suggests that COVID-19 anosmia is not only due to neurotropism and the direct action of SARS-CoV-2 entering the olfactory bulb. The mechanism of SARS-CoV-2 neuropathogenesis in the olfactory bulb requires a better elucidation and further research studies to mitigate the olfactory bulb damage associated with virus action.
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Affiliation(s)
- Marco Dell’Aquila
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
- Pathology Unit, Belcolle Hospital, ASL Viterbo, 01100 Viterbo, Italy
| | - Concetta Cafiero
- Medical Oncology, SG Moscati Hospital, 74010 Statte, Italy;
- Anatomic Pathology Unit, Fabrizio Spaziani Hospital, 03100 Frosinone, Italy
| | - Alessandra Micera
- Research and Development Laboratory for Biochemical, Molecular and Cellular Applications in Ophthalmological Science, IRCCS–Fondazione Bietti, 00184 Rome, Italy
| | - Egidio Stigliano
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
| | - Maria Pia Ottaiano
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Giulio Benincasa
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Beniamino Schiavone
- Department of Clinical Pathology and Molecular Biology, Pineta Grande Hospital, 81030 Castel Volturno, Italy; (M.P.O.); (G.B.); (B.S.)
| | - Leo Guidobaldi
- Cytodiagnostic Unit, Section of Pathology Sandro Pertini Hospital, ASL Rm2, 00157 Rome, Italy;
| | - Luigi Santacroce
- Section of Microbiology and Virology, Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | | | - Vincenzo Arena
- Anatomic Pathology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy; (M.D.); (E.S.); (V.A.)
| | - Raffaele Palmirotta
- Section of Sciences and Technologies of Laboratory Medicine, Interdisciplinary Department of Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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10
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Wu ML, Xie C, Li X, Sun J, Zhao J, Wang JH. Mast cell activation triggered by SARS-CoV-2 causes inflammation in brain microvascular endothelial cells and microglia. Front Cell Infect Microbiol 2024; 14:1358873. [PMID: 38638822 PMCID: PMC11024283 DOI: 10.3389/fcimb.2024.1358873] [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: 12/20/2023] [Accepted: 03/15/2024] [Indexed: 04/20/2024] Open
Abstract
SARS-CoV-2-induced excessive inflammation in brain leads to damage of blood-brain barrier, hypoxic-ischemic injury, and neuron degeneration. The production of inflammatory cytokines by brain microvascular endothelial cells and microglia is reported to be critically associated with the brain pathology of COVID-19 patients. However, the cellular mechanisms for SARS-CoV-2-inducing activation of brain cells and the subsequent neuroinflammation remain to be fully delineated. Our research, along with others', has recently demonstrated that SARS-CoV-2-induced accumulation and activation of mast cells (MCs) in mouse lung could further induce inflammatory cytokines and consequent lung damages. Intracerebral MCs activation and their cross talk with other brain cells could induce neuroinflammation that play important roles in neurodegenerative diseases including virus-induced neuro-pathophysiology. In this study, we investigated the role of MC activation in SARS-CoV-2-induced neuroinflammation. We found that (1) SARS-CoV-2 infection triggered MC accumulation in the cerebrovascular region of mice; (2) spike/RBD (receptor-binding domain) protein-triggered MC activation induced inflammatory factors in human brain microvascular endothelial cells and microglia; (3) MC activation and degranulation destroyed the tight junction proteins in brain microvascular endothelial cells and induced the activation and proliferation of microglia. These findings reveal a cellular mechanism of SARS-CoV-2-induced neuroinflammation.
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Affiliation(s)
- Meng-Li Wu
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Chengzuo Xie
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xin Li
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Jing Sun
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jincun Zhao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jian-Hua Wang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- University of Chinese Academy of Sciences, Beijing, China
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11
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Chang K, Zaikos T, Kilner-Pontone N, Ho CY. Mechanisms of COVID-19-associated olfactory dysfunction. Neuropathol Appl Neurobiol 2024; 50:e12960. [PMID: 38419211 PMCID: PMC10906737 DOI: 10.1111/nan.12960] [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: 06/15/2023] [Revised: 12/26/2023] [Accepted: 01/08/2024] [Indexed: 03/02/2024]
Abstract
Olfactory dysfunction is one of the most common symptoms of COVID-19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID-19-associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID-19-associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long-term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID-19-associated olfactory dysfunction.
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Affiliation(s)
- Koping Chang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department and Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Thomas Zaikos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Cheng-Ying Ho
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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12
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Massimi L, Cinalli G, Frassanito P, Arcangeli V, Auer C, Baro V, Bartoli A, Bianchi F, Dietvorst S, Di Rocco F, Gallo P, Giordano F, Hinojosa J, Iglesias S, Jecko V, Kahilogullari G, Knerlich-Lukoschus F, Laera R, Locatelli D, Luglietto D, Luzi M, Messing-Jünger M, Mura R, Ragazzi P, Riffaud L, Roth J, Sagarribay A, Pinheiro MS, Spazzapan P, Spennato P, Syrmos N, Talamonti G, Valentini L, Van Veelen ML, Zucchelli M, Tamburrini G. Intracranial complications of sinogenic and otogenic infections in children: an ESPN survey on their occurrence in the pre-COVID and post-COVID era. Childs Nerv Syst 2024; 40:1221-1237. [PMID: 38456922 DOI: 10.1007/s00381-024-06332-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND COVID-19 pandemic is thought to have changed the epidemiology of some pediatric neurosurgical disease: among them are the intracranial complications of sinusitis and otitis (ICSO). According to some studies on a limited number of cases, both streptococci-related sinusitis and ICSO would have increased immediately after the pandemic, although the reason is not clear yet (seasonal changes versus pandemic-related effects). The goal of the present survey of the European Society for Pediatric Neurosurgery (ESPN) was to collect a large number of cases from different European countries encompassing the pre-COVID (2017-2019), COVID (2020-2021), and post-COVID period (2022-June 2023) looking for possible epidemiological and/or clinical changes. MATERIAL AND METHODS An English language questionnaire was sent to ESPN members about year of the event, patient's age and gender, presence of immune-deficit or other favoring risk factors, COVID infection, signs and symptoms at onset, site of primary infection, type of intracranial complication, identified germ, type and number of surgical operations, type and duration of medical treatment, clinical and radiological outcome, duration of the follow-up. RESULTS Two hundred fifty-four cases were collected by 30 centers coming from 14 different European countries. There was a statistically significant difference between the post-COVID period (129 children, 86 cases/year, 50.7% of the whole series) and the COVID (40 children, 20 cases/year, 15.7%) or the pre-COVID period (85 children, 28.3 cases/year, 33.5%). Other significant differences concerned the presence of predisposing factors/concurrent diseases (higher in the pre-COVID period) and previous COVID infection (higher in the post-COVID period). No relevant differences occurred as far as demographic, microbiological, clinical, radiological, outcome, morbidity, and mortality data were concerned. Paranasal sinuses and middle ear/mastoid were the most involved primary site of infection (71% and 27%, respectively), while extradural or subdural empyema and brain abscess were the most common ICSO (73% and 17%, respectively). Surgery was required in 95% of cases (neurosurgical and ENT procedure in 71% and 62% of cases, respectively) while antibiotics in 99% of cases. After a 12.4-month follow-up, a full clinical and radiological recovery was obtained in 85% and 84% of cases, respectively. The mortality rate was 2.7%. CONCLUSIONS These results suggest that the occurrence of ICSO was significantly increased after the pandemic. Such an increase seems to be related to the indirect effects of the pandemic (e.g., immunity debt) rather than to a direct effect of COVID infection or to seasonal fluctuations. ICSO remain challenging diseases but the pandemic did not affect the management strategies nor their prognosis. The epidemiological change of sinusitis/otitis and ICSO should alert about the appropriate follow-up of children with sinusitis/otitis.
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Affiliation(s)
- L Massimi
- Pediatric Neurosurgery, Neuroscience-Sense Organs-Chest Department, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Neuroscience, Catholic University Medical School, Rome, Italy
| | - G Cinalli
- Santobono-Pausilipon Children's Hospital, AORN, Naples, Italy
| | - P Frassanito
- Pediatric Neurosurgery, Neuroscience-Sense Organs-Chest Department, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - V Arcangeli
- Clinical Psychology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - C Auer
- Department of Neurosurgery, Johannes Kepler University Linz, Kepler University Hospital GmbH, Linz, Austria
| | - V Baro
- Pediatric and Functional Neurosurgery, Department of Neurosciences, University of Padova, Padua, Italy
| | - A Bartoli
- Department of Neurosurgery, Geneva University Hospitals, Geneva, Switzerland
| | - F Bianchi
- Pediatric Neurosurgery, Neuroscience-Sense Organs-Chest Department, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - S Dietvorst
- University Hospitals Leuven, Leuven, Belgium
| | - F Di Rocco
- Hôpital Femme-Mère-Enfant, Université de Lyon, Lyon, France
| | - P Gallo
- Birmingham Children's Hospital, Birmingham, UK
| | - F Giordano
- University of Florence, Florence, Italy
- Meyer Children's Hospital IRCCS, Florence, Italy
| | - J Hinojosa
- Hospital Sant Joan de Déu, Barcelona, Spain
| | - S Iglesias
- Hospital Regional Universitario de Malaga, Malaga, Spain
| | - V Jecko
- Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - G Kahilogullari
- Department of Neurosurgery, Ankara University, Ankara, Turkey
| | - F Knerlich-Lukoschus
- Division Pediatric Neurosurgery, Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - R Laera
- Santobono-Pausilipon Children's Hospital, AORN, Naples, Italy
| | - D Locatelli
- Neurosurgery Department, Università Dell'Insubria, Ospedale di Circolo e Macchi Foundation, Varese, Italy
| | - D Luglietto
- Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - M Luzi
- Azienda Ospedaliero Universitaria Delle Marche, Ancona, Italy
| | | | - R Mura
- Meyer Children's Hospital IRCCS, Florence, Italy
| | - P Ragazzi
- Department of Pediatric Neurosurgery, Ospedale Infantile Regina Margherita, Città della Salute e della Scienza, Turin, Italy
| | - L Riffaud
- Rennes University Hospital, Rennes, France
| | - J Roth
- Dana Children's Hospital, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - A Sagarribay
- Hospital Dona Estefânia-Centro Hospitalar Universitário, Lisboa, Portugal
- Hospital CUF Descobertas, Lisboa, Portugal
| | - M Santos Pinheiro
- Centro Hospitalar Lisboa Norte-Hospital Santa Maria, Lisboa, Portugal
| | - P Spazzapan
- University Medical Center-Ljubljana, Ljubljana, Slovenia
| | - P Spennato
- Santobono-Pausilipon Children's Hospital, AORN, Naples, Italy
| | - N Syrmos
- Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - L Valentini
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - M L Van Veelen
- Erasmus MC Sophia Children's Hospital, Rotterdam, Netherlands
| | - M Zucchelli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto Scienze Neurologiche Di Bologna, Boulogne, Italy
| | - G Tamburrini
- Pediatric Neurosurgery, Neuroscience-Sense Organs-Chest Department, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Department of Neuroscience, Catholic University Medical School, Rome, Italy
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13
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Magaki S, Zhang T, Han K, Hilda M, Yong WH, Achim C, Fishbein G, Fishbein MC, Garner O, Salamon N, Williams CK, Valdes-Sueiras MA, Hsu JJ, Kelesidis T, Mathisen GE, Lavretsky H, Singer EJ, Vinters HV. HIV and COVID-19: two pandemics with significant (but different) central nervous system complications. FREE NEUROPATHOLOGY 2024; 5:5-5. [PMID: 38469363 PMCID: PMC10925920 DOI: 10.17879/freeneuropathology-2024-5343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 03/02/2024] [Indexed: 03/13/2024]
Abstract
Human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause significant neurologic disease. Central nervous system (CNS) involvement of HIV has been extensively studied, with well-documented invasion of HIV into the brain in the initial stage of infection, while the acute effects of SARS-CoV-2 in the brain are unclear. Neuropathologic features of active HIV infection in the brain are well characterized whereas neuropathologic findings in acute COVID-19 are largely non-specific. On the other hand, neuropathologic substrates of chronic dysfunction in both infections, as HIV-associated neurocognitive disorders (HAND) and post-COVID conditions (PCC)/long COVID are unknown. Thus far, neuropathologic studies on patients with HAND in the era of combined antiretroviral therapy have been inconclusive, and autopsy studies on patients diagnosed with PCC have yet to be published. Further longitudinal, multidisciplinary studies on patients with HAND and PCC and neuropathologic studies in comparison to controls are warranted to help elucidate the mechanisms of CNS dysfunction in both conditions.
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Affiliation(s)
- Shino Magaki
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
| | - Ting Zhang
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
| | - Karam Han
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
| | - Mirbaha Hilda
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
| | - William H. Yong
- Department of Pathology and Laboratory Medicine, University of California-Irvine School of Medicine, Irvine, CA, USA
| | - Cristian Achim
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, USA
| | - Gregory Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Michael C. Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Omai Garner
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Noriko Salamon
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Christopher K. Williams
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
| | - Miguel A. Valdes-Sueiras
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jeffrey J. Hsu
- Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Theodoros Kelesidis
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Glenn E. Mathisen
- Department of Infectious Diseases, Olive View-University of California Los Angeles Medical Center, Sylmar, CA, USA
| | - Helen Lavretsky
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Elyse J. Singer
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Harry V. Vinters
- Section of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles CA, USA
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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14
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VanElzakker MB, Bues HF, Brusaferri L, Kim M, Saadi D, Ratai EM, Dougherty DD, Loggia ML. Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [ 11C]PBR28 PET correlates with vascular disease measures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.19.563117. [PMID: 37905031 PMCID: PMC10614970 DOI: 10.1101/2023.10.19.563117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.
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Affiliation(s)
- Michael B VanElzakker
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- PolyBio Research Foundation, Medford, MA, USA
| | - Hannah F Bues
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ludovica Brusaferri
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Computer Science And Informatics, School of Engineering, London South Bank University, London, UK
| | - Minhae Kim
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Deena Saadi
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Eva-Maria Ratai
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Darin D Dougherty
- Division of Neurotherapeutics, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Marco L Loggia
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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15
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Pileggi CA, Parmar G, Elkhatib H, Stewart CM, Alecu I, Côté M, Bennett SA, Sandhu JK, Cuperlovic-Culf M, Harper ME. The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics. CURRENT RESEARCH IN NEUROBIOLOGY 2023; 5:100112. [PMID: 38020812 PMCID: PMC10663135 DOI: 10.1016/j.crneur.2023.100112] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 08/21/2023] [Accepted: 09/25/2023] [Indexed: 12/01/2023] Open
Abstract
SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.
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Affiliation(s)
- Chantal A. Pileggi
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- National Research Council of Canada, Digital Technologies Research Centre, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Gaganvir Parmar
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
| | - Hussein Elkhatib
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
| | - Corina M. Stewart
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Current Address: Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Irina Alecu
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Neural Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Marceline Côté
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, ON, K1H 8M5, Canada
| | - Steffany A.L. Bennett
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Neural Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Jagdeep K. Sandhu
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, ON, K1H 8M5, Canada
- Human Health Therapeutics Research Centre, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Miroslava Cuperlovic-Culf
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- National Research Council of Canada, Digital Technologies Research Centre, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada
| | - Mary-Ellen Harper
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, ON, K1H 8M5, Canada
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16
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Wei ZYD, Liang K, Shetty AK. Complications of COVID-19 on the Central Nervous System: Mechanisms and Potential Treatment for Easing Long COVID. Aging Dis 2023; 14:1492-1510. [PMID: 37163427 PMCID: PMC10529748 DOI: 10.14336/ad.2023.0312] [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: 01/20/2023] [Accepted: 03/12/2023] [Indexed: 05/12/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades human cells by binding to the angiotensin-converting-enzyme-2 (ACE-2) using a spike protein and leads to Coronavirus disease-2019 (COVID-19). COVID-19 primarily causes a respiratory infection that can lead to severe systemic inflammation. It is also common for some patients to develop significant neurological and psychiatric symptoms. The spread of SARS-CoV-2 to the CNS likely occurs through several pathways. Once spread in the CNS, many acute symptoms emerge, and such infections could also transpire into severe neurological complications, including encephalitis or ischemic stroke. After recovery from the acute infection, a significant percentage of patients develop "long COVID," a condition in which several symptoms of COVID-19 persist for prolonged periods. This review aims to discuss acute and chronic neurological problems after SARS-CoV-2 infection. The potential mechanisms by which SARS-CoV-2 enters the CNS and causes neuroinflammation, neuropathological changes observed in post-mortem brains of COVID-19 patients, and cognitive and mood problems in COVID-19 survivors are discussed in the initial part. The later part of the review deliberates the causes of long COVID, approaches for noninvasive tracking of neuroinflammation in long COVID patients, and the potential therapeutic strategies that could ease enduring CNS symptoms observed in long COVID.
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Affiliation(s)
- Zhuang-Yao D Wei
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Health Science Center School of Medicine, College Station, TX, USA
| | - Ketty Liang
- Sam Houston State University College of Osteopathic Medicine, Conroe, TX, USA
| | - Ashok K Shetty
- Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Health Science Center School of Medicine, College Station, TX, USA
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17
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Ju H, Kim YH, Seok JM, Kim BJ. Unusual Demyelinating Disease of the Central Nervous System Involving Bilateral Corticospinal Tracts Following COVID-19 Infection: A Case Report. J Clin Neurol 2023; 19:503-505. [PMID: 37635429 PMCID: PMC10471557 DOI: 10.3988/jcn.2023.0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/26/2023] [Accepted: 06/05/2023] [Indexed: 08/29/2023] Open
Affiliation(s)
- Hyunjin Ju
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Korea
| | - Young Hun Kim
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Korea
| | - Jin Myoung Seok
- Department of Neurology, Soonchunhyang University Hospital Cheonan, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Byoung Joon Kim
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Korea.
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18
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Krishna VD, Chang A, Korthas H, Var SR, Low WC, Li L, Cheeran MCJ. Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.11.552998. [PMID: 37645925 PMCID: PMC10462071 DOI: 10.1101/2023.08.11.552998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for the worldwide COVID-19 pandemic, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe disease, and sexual dimorphism in clinical outcomes has been reported in COVID-19. SARS-CoV-2 infection in humans can cause damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with COVID-19, with many survivors suffering from persistent neurological and cognitive impairment, potentially accelerating Alzheimer's disease. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6 mice were inoculated, by intranasal route, with SARS-CoV-2 lineage B.1.351 variant known to infect mice. Older animals and in particular males exhibited a significantly greater weight loss starting at 4 dpi. In addition, male animals exhibited higher viral RNA loads and higher titers of infectious virus in the lung, which was particularly evident in males at 16 months of age. Notably, no viral RNA was detected in the brains of infected mice, regardless of age or sex. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain was increased with viral infection. An unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles in the brain, with innate immunity, defense response to virus, cerebravascular and neuronal functions, as the major molecular networks affected. The data presented in this study show that SARS-CoV-2 infection triggers a neuroinflammatory response despite the lack of detectable virus in the brain. Age and sex have a modifying effect on this pathogenic process. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and supression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.
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Affiliation(s)
- Venkatramana D. Krishna
- Department of Veterinary Population Medicine, University of Minnesota, Saint Paul, MN 55108, USA
| | | | - Holly Korthas
- Department of Experimental and Clinical Pharmacology
| | - Susanna R. Var
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Walter C. Low
- Graduate Program in Neuroscience
- Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ling Li
- Graduate Program in Neuroscience
- Department of Experimental and Clinical Pharmacology
| | - Maxim C-J. Cheeran
- Department of Veterinary Population Medicine, University of Minnesota, Saint Paul, MN 55108, USA
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19
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Li R, Liu G, Zhang X, Zhang M, Lu J, Li H. Altered intrinsic brain activity and functional connectivity in COVID-19 hospitalized patients at 6-month follow-up. BMC Infect Dis 2023; 23:521. [PMID: 37553613 PMCID: PMC10410836 DOI: 10.1186/s12879-023-08331-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 05/15/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Although most patients can recover from SARS-CoV-2 infection during the short-term, the long-term effects of COVID-19 on the brain remain explored. Functional MRI (fMRI) could potentially elucidate or otherwise contribute to the investigation of the long COVID syndrome. A lower fMRI response would be translated into decreased brain activity or delayed signal transferring reflecting decreased connectivity. This research aimed to investigate the long-term alterations in the local (regional) brain activity and remote (interregional) functional connection in recovered COVID-19. METHODS Thirty-five previously hospitalized COVID-19 patients underwent 3D T1weighed imaging and resting-state fMRI at 6-month follow-up, and 36 demographic-matched healthy controls (HCs) were recruited accordingly. The amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) was used to assess the regional intrinsic brain activity and the influence of regional disturbances on FC with other brain regions. Spearman correlation analyses were performed to evaluate the association between brain function changes and clinical variables. RESULTS The incidence of neurosymptoms (6/35, 17.14%) decreased significantly at 6-month follow-up, compared with COVID-19 hospitalization stage (21/35, 60%). Compared with HCs, recovered COVID-19 exhibited higher ALFF in right precuneus, middle temporal gyrus, middle and inferior occipital gyrus, lower ALFF in right middle frontal gyrus and bilateral inferior temporal gyrus. Furthermore, setting seven abnormal activity regions as seeds, we found increased FC between right middle occipital gyrus and left inferior occipital gyrus, and reduced FC between right inferior occipital gyrus and right inferior temporal gyrus/bilateral fusiform gyrus, and between right middle frontal gyrus and right middle frontal gyrus/ supplementary motor cortex/ precuneus. Additionally, abnormal ALFF and FC were associated with clinical variables. CONCLUSIONS COVID-19 related neurological symptoms can self heal over time. Recovered COVID-19 presented functional alterations in right frontal, temporal and occipital lobe at 6-month follow-up. Most regional disturbances in ALFF were related to the weakening of short-range regional interactions in the same brain function.
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Affiliation(s)
- Ruili Li
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing, 100053, China
- Department of Radiology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao Youanmen Wai, Fengtai District, Beijing, 100069, China
- Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, 100053, China
| | - Guangxue Liu
- Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Xiaodong Zhang
- Department of Radiology, Tianjin First Central Hospital, Nankai University, Tianjin, 300192, China
| | - Miao Zhang
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing, 100053, China
- Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, 100053, China
| | - Jie Lu
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing, 100053, China.
- Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, 100053, China.
| | - Hongjun Li
- Department of Radiology, Beijing Youan Hospital, Capital Medical University, No.8 Xi Tou Tiao Youanmen Wai, Fengtai District, Beijing, 100069, China.
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20
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De Neck S, Penrice-Randal R, Clark JJ, Sharma P, Bentley EG, Kirby A, Mega DF, Han X, Owen A, Hiscox JA, Stewart JP, Kipar A. The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections. Viruses 2023; 15:1637. [PMID: 37631979 PMCID: PMC10458810 DOI: 10.3390/v15081637] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/14/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
The respiratory system is the main target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19) where acute respiratory distress syndrome is considered the leading cause of death. Changes in pulmonary blood vessels, among which an endothelialitis/endotheliitis has been particularly emphasized, have been suggested to play a central role in the development of acute lung injury. Similar vascular changes are also observed in animal models of COVID-19. The present study aimed to determine whether the latter are specific for SARS-CoV-2 infection, investigating the vascular response in the lungs of mice infected with SARS-CoV-2 and other respiratory viruses (influenza A and murine gammaherpesvirus) by in situ approaches (histology, immunohistology, morphometry) combined with RNA sequencing and bioinformatic analysis. Non-selective recruitment of monocytes and T and B cells from larger muscular veins and arteries was observed with all viruses, matched by a comparable transcriptional response. There was no evidence of endothelial cell infection in any of the models. Both the morphological investigation and the transcriptomics approach support the interpretation that the lung vasculature in mice mounts a stereotypic response to alveolar and respiratory epithelial damage. This may have implications for the treatment and management of respiratory disease in humans.
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Affiliation(s)
- Simon De Neck
- Laboratory for Animal Model Pathology, Vetsuisse Faculty, Institute of Veterinary Pathology, University of Zurich, 8057 Zurich, Switzerland;
| | - Rebekah Penrice-Randal
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Jordan J. Clark
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Parul Sharma
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Eleanor G. Bentley
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Adam Kirby
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Daniele F. Mega
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Ximeng Han
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Andrew Owen
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L3 3RF, UK;
| | - Julian A. Hiscox
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - James P. Stewart
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
| | - Anja Kipar
- Laboratory for Animal Model Pathology, Vetsuisse Faculty, Institute of Veterinary Pathology, University of Zurich, 8057 Zurich, Switzerland;
- Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L3 3RF, UK; (R.P.-R.); (J.J.C.); (P.S.); (E.G.B.); (A.K.); (D.F.M.); (X.H.); (J.A.H.); (J.P.S.)
- Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, University of Helsinki, 00790 Helsinki, Finland
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21
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Hameed R, Bahadur AR, Singh SB, Sher J, Todua M, Moradi L(M, Bastakoti S, Arslan M, Ajmal H, Lee GY, Ayubcha C, Werner TJ, Alavi A, Revheim ME. Neurological and Psychiatric Manifestations of Long COVID-19 and Their [ 18F]FDG PET Findings: A Review. Diagnostics (Basel) 2023; 13:2353. [PMID: 37510097 PMCID: PMC10378471 DOI: 10.3390/diagnostics13142353] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/05/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
For more than two years, lingering sequalae of COVID-19 have been extensively investigated. Approximately 10% of individuals infected by COVID-19 have been found to experience long-term symptoms termed "long COVID-19". The neurological and psychiatric manifestations of long COVID-19 are of particular concern. While pathogenesis remains unclear, emerging imaging studies have begun to better elucidate certain pathological manifestation. Of specific interest is imaging with [18F]FDG PET which directly reflects cellular glycolysis often linked to metabolic and inflammatory processes. Seeking to understand the molecular basis of neurological features of long COVID-19, this review encompasses the most recent [18F]FDG PET literature in this area.
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Affiliation(s)
- Rizwanullah Hameed
- Kingsbrook Jewish Medical Center, 585 Schenectady Avenue, New York, NY 11203, USA;
- Interfaith Medical Center, 1545 Atlantic Avenue, New York, NY 11213, USA
| | | | - Shashi Bhushan Singh
- Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304, USA;
| | - Juwairah Sher
- Medical University of the Americas, 27 Jackson Road, Suite 302, Devens, MA 0134, USA;
| | - Maia Todua
- Department of Endocrinology, Tbilisi State Medical University, Vazha-Pshavela Ave. 33, 0186 Tbilisi, Georgia;
| | - Leah (Mahsa) Moradi
- Touro University, Touro College of Pharmacy, 3 Times Square, New York, NY 10036, USA;
| | | | - Maeen Arslan
- Dartmouth College Hanover, Hanover, NH 03755, USA;
| | - Hanfa Ajmal
- College of Public Health, University of South Florida, 4202 E Fowler Ave., Tampa, FL 33620, USA;
| | - Gha Young Lee
- Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; (G.Y.L.); (C.A.)
| | - Cyrus Ayubcha
- Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; (G.Y.L.); (C.A.)
| | - Thomas J. Werner
- Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USA; (T.J.W.); (A.A.)
| | - Abass Alavi
- Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USA; (T.J.W.); (A.A.)
| | - Mona-Elisabeth Revheim
- The Intervention Center, Rikshospitalet, Division for Technology and Innovation, Oslo University Hospital, 0424 Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0313 Oslo, Norway
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22
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Hall BJ, Duddy JC, Apostolopoulou K, David R, Kurzbuch A, Nadkarni A, Trichinopoly Krishna S, Cooper B, Gouldbourne H, Hennigan D, Dawes W, Ellenbogen J, Parks C, Pettorini B, Sinha A, Mallucci C. Intracranial Empyemas in the COVID-19 Era: A New Phenomenon? A Paediatric Case Series and Review of the Literature. Pediatr Neurosurg 2023; 58:215-222. [PMID: 37393893 PMCID: PMC10614506 DOI: 10.1159/000531753] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 06/01/2023] [Indexed: 07/04/2023]
Abstract
INTRODUCTION We present the largest series of paediatric intracranial empyemas occurring after COVID-19 infection to date, and discuss the potential implications of the pandemic on this neurosurgical pathology. METHODS Patients admitted to our centre between January 2016 and December 2021 with a confirmed radiological diagnosis of intracranial empyema were retrospectively reviewed, excluding non-otorhinological source cases. Patients were grouped according to onset before or after onset of the COVID-19 pandemic and COVID-19 status. A literature review of all post-COVID-19 intracranial empyemas was performed. SPSS v27 was used for statistical analysis. RESULTS Sixteen patients were diagnosed with intracranial empyema: n = 5 prior to 2020 and n = 11 after, resulting in an average annual incidence of 0.3% prior to onset of the pandemic and 1.2% thereafter. Of those diagnosed since the pandemic, 4 (25%) were confirmed to have COVID-19 on recent PCR test. Time from COVID-19 infection until empyema diagnosis ranged from 15 days to 8 weeks. Mean age for post-COVID-19 cases was 8.5 years (range: 7-10 years) compared to 11 years in non-COVID cases (range: 3-14 years). Streptococcus intermedius was grown in all cases of post-COVID-19 empyema, and 3 of 4 (75%) post-COVID-19 cases developed cerebral sinus thromboses, compared to 3 of 12 (25%) non-COVID-19 cases. All cases were discharged home with no residual deficit. CONCLUSION Our post-COVID-19 intracranial empyema series demonstrates a greater proportion of cerebral sinus thromboses than non-COVID-19 cases, potentially reflecting the thrombogenic effects of COVID-19. Incidence of intracranial empyema at our centre has increased since the start of the pandemic, causes of which require further investigation and multicentre collaboration.
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Affiliation(s)
- Benjamin J Hall
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - John C Duddy
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Katerina Apostolopoulou
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Raenette David
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Arthur Kurzbuch
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Abhishek Nadkarni
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | | | - Ben Cooper
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Hayley Gouldbourne
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Dawn Hennigan
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - William Dawes
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Jonathan Ellenbogen
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Christopher Parks
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Benedetta Pettorini
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Ajay Sinha
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
| | - Conor Mallucci
- Department of Neurosurgery, Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK
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23
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Visvabharathy L, Hanson BA, Orban ZS, Lim PH, Palacio NM, Jimenez M, Clark JR, Graham EL, Liotta EM, Tachas G, Penaloza-MacMaster P, Koralnik IJ. Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein. Front Immunol 2023; 14:1155770. [PMID: 37313412 PMCID: PMC10258318 DOI: 10.3389/fimmu.2023.1155770] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/11/2023] [Indexed: 06/15/2023] Open
Abstract
Introduction Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. Results We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. Discussion We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.
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Affiliation(s)
- Lavanya Visvabharathy
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Barbara A. Hanson
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Zachary S. Orban
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Patrick H. Lim
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Nicole M. Palacio
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Millenia Jimenez
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Jeffrey R. Clark
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Edith L. Graham
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Eric M. Liotta
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - George Tachas
- Drug Discovery & Patents, Antisense Therapeutics Ltd., Melbourne, VIC, Australia
| | - Pablo Penaloza-MacMaster
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Igor J. Koralnik
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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24
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Alabsi H, Emerson K, Lin DJ. Neurorecovery after Critical COVID-19 Illness. Semin Neurol 2023. [PMID: 37168008 DOI: 10.1055/s-0043-1768714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
With the hundreds of millions of people worldwide who have been, and continue to be, affected by pandemic coronavirus disease (COVID-19) and its chronic sequelae, strategies to improve recovery and rehabilitation from COVID-19 are critical global public health priorities. Neurologic complications have been associated with acute COVID-19 infection, usually in the setting of critical COVID-19 illness. Neurologic complications are also a core feature of the symptom constellation of long COVID and portend poor outcomes. In this article, we review neurologic complications and their mechanisms in critical COVID-19 illness and long COVID. We focus on parallels with neurologic disease associated with non-COVID critical systemic illness. We conclude with a discussion of how recent findings can guide both neurologists working in post-acute neurologic rehabilitation facilities and policy makers who influence neurologic resource allocation.
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Affiliation(s)
- Haitham Alabsi
- Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kristi Emerson
- Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - David J Lin
- Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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25
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Haddad M, Sheybani F, Olfati N, Nahayati MA, Boostani R, Layegh P, Rashid-Nejad A. Central nervous system reactivation of herpesviridae family in patients with COVID-19. J Neurovirol 2023; 29:211-217. [PMID: 37097596 PMCID: PMC10127951 DOI: 10.1007/s13365-023-01132-4] [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: 07/13/2022] [Revised: 03/05/2023] [Accepted: 03/28/2023] [Indexed: 04/26/2023]
Abstract
The objective of this study is to describe our COVID-19 patients with herpesviridae reactivation in the central nervous system (CNS). Four patients were described including two with acute encephalitis and two with acute encephalomyelitis. Three of four patients had abnormal findings on neuroimaging studies. One of four patients died, one survived with major neurological sequelae, and two others fully recovered. Herpesviridae reactivation in the CNS in patients with COVID-19 is a rare but serious coincidence. The optimal therapeutic management has not been investigated and until more information is available, it is prudent to treat these patients with appropriate antivirals with or without anti-inflammatory agents.
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Affiliation(s)
- Mahboubeh Haddad
- Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fereshte Sheybani
- Department of Infectious Diseases and Tropical Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Nahid Olfati
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Ali Nahayati
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Boostani
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Layegh
- Department of Radiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azra Rashid-Nejad
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Gelpi E, Klotz S, Beyerle M, Wischnewski S, Harter V, Kirschner H, Stolz K, Reisinger C, Lindeck-Pozza E, Zoufaly A, Leoni M, Gorkiewicz G, Zacharias M, Haberler C, Hainfellner J, Woehrer A, Hametner S, Roetzer T, Voigtländer T, Ricken G, Endmayr V, Haider C, Ludwig J, Polt A, Wilk G, Schmid S, Erben I, Nguyen A, Lang S, Simonitsch-Klupp I, Kornauth C, Nackenhorst M, Kläger J, Kain R, Chott A, Wasicky R, Krause R, Weiss G, Löffler-Rag J, Berger T, Moser P, Soleiman A, Asslaber M, Sedivy R, Klupp N, Klimpfinger M, Risser D, Budka H, Schirmer L, Pröbstel AK, Höftberger R. Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence. Viruses 2023; 15:908. [PMID: 37112888 PMCID: PMC10144140 DOI: 10.3390/v15040908] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. METHODS We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. RESULTS All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). CONCLUSIONS Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.
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Affiliation(s)
- Ellen Gelpi
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Sigrid Klotz
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Miriam Beyerle
- Departments of Neurology, Biomedicine and Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland; (M.B.); (A.-K.P.)
- Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Department of Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland;
| | - Sven Wischnewski
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
- Mannheim Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Verena Harter
- Department of Pathology, Klinik Favoriten, 1100 Vienna, Austria (H.K.); (R.S.); (M.K.)
| | - Harald Kirschner
- Department of Pathology, Klinik Favoriten, 1100 Vienna, Austria (H.K.); (R.S.); (M.K.)
| | - Katharina Stolz
- Department of Forensic Medicine, Medical University of Vienna, 1090 Vienna, Austria; (K.S.); (C.R.); (N.K.); (D.R.)
| | - Christoph Reisinger
- Department of Forensic Medicine, Medical University of Vienna, 1090 Vienna, Austria; (K.S.); (C.R.); (N.K.); (D.R.)
| | | | - Alexander Zoufaly
- Intensive Care Unit, Klinik Favoriten, 1100 Vienna, Austria;
- Faculty of Medicine, Sigmund Freud University, 1020 Vienna, Austria
| | - Marlene Leoni
- D&F Institute of Pathology, Neuropathology, Medical University Graz, 8036 Graz, Austria; (M.L.); (G.G.); (M.Z.); (M.A.)
| | - Gregor Gorkiewicz
- D&F Institute of Pathology, Neuropathology, Medical University Graz, 8036 Graz, Austria; (M.L.); (G.G.); (M.Z.); (M.A.)
| | - Martin Zacharias
- D&F Institute of Pathology, Neuropathology, Medical University Graz, 8036 Graz, Austria; (M.L.); (G.G.); (M.Z.); (M.A.)
| | - Christine Haberler
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Johannes Hainfellner
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Adelheid Woehrer
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Simon Hametner
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Roetzer
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Till Voigtländer
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Gerda Ricken
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Verena Endmayr
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Carmen Haider
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Judith Ludwig
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Andrea Polt
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Gloria Wilk
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Susanne Schmid
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Irene Erben
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Anita Nguyen
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Susanna Lang
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Ingrid Simonitsch-Klupp
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Christoph Kornauth
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
- Münchner Leukämielabor, 81377 Munich, Germany
| | - Maja Nackenhorst
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Johannes Kläger
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Andreas Chott
- Institute of Pathology, Klinik Ottakring, 1160 Vienna, Austria; (A.C.); (R.W.)
| | - Richard Wasicky
- Institute of Pathology, Klinik Ottakring, 1160 Vienna, Austria; (A.C.); (R.W.)
| | - Robert Krause
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
| | - Günter Weiss
- Department of Internal Medicine and Pulmonology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (G.W.); (J.L.-R.)
| | - Judith Löffler-Rag
- Department of Internal Medicine and Pulmonology, Medical University of Innsbruck, 6020 Innsbruck, Austria; (G.W.); (J.L.-R.)
| | - Thomas Berger
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
- Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
| | - Patrizia Moser
- Department of Neuropathology, Tirol Kliniken GmbH, 6020 Innsbruck, Austria; (P.M.); (A.S.)
| | - Afshin Soleiman
- Department of Neuropathology, Tirol Kliniken GmbH, 6020 Innsbruck, Austria; (P.M.); (A.S.)
| | - Martin Asslaber
- D&F Institute of Pathology, Neuropathology, Medical University Graz, 8036 Graz, Austria; (M.L.); (G.G.); (M.Z.); (M.A.)
| | - Roland Sedivy
- Department of Pathology, Klinik Favoriten, 1100 Vienna, Austria (H.K.); (R.S.); (M.K.)
| | - Nikolaus Klupp
- Department of Forensic Medicine, Medical University of Vienna, 1090 Vienna, Austria; (K.S.); (C.R.); (N.K.); (D.R.)
| | - Martin Klimpfinger
- Department of Pathology, Klinik Favoriten, 1100 Vienna, Austria (H.K.); (R.S.); (M.K.)
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (S.L.); (I.S.-K.); (C.K.); (M.N.); (R.K.)
| | - Daniele Risser
- Department of Forensic Medicine, Medical University of Vienna, 1090 Vienna, Austria; (K.S.); (C.R.); (N.K.); (D.R.)
| | - Herbert Budka
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
| | - Lucas Schirmer
- Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Department of Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland;
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Anne-Katrin Pröbstel
- Departments of Neurology, Biomedicine and Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland; (M.B.); (A.-K.P.)
- Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Department of Clinical Research, University Hospital and University of Basel, 4031 Basel, Switzerland;
| | - Romana Höftberger
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria; (S.K.); (C.H.); (J.H.); (A.W.); (S.H.); (T.R.); (T.V.); (V.E.); (C.H.); (J.L.); (A.P.); (G.W.); (S.S.); (I.E.); (A.N.); (T.B.); (H.B.)
- Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, 1090 Vienna, Austria
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27
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Asakawa T, Cai Q, Shen J, Zhang Y, Li Y, Chen P, Luo W, Zhang J, Zhou J, Zeng H, Weng R, Hu F, Feng H, Chen J, Huang J, Zhang X, Zhao Y, Fang L, Yang R, Huang J, Wang F, Liu Y, Lu H. Sequelae of long COVID, known and unknown: A review of updated information. Biosci Trends 2023; 17:85-116. [PMID: 36928222 DOI: 10.5582/bst.2023.01039] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
Over three years have passed since the COVID-19 pandemic started. The dangerousness and impact of COVID-19 should definitely not be ignored or underestimated. Other than the symptoms of acute infection, the long-term symptoms associated with SARS-CoV-2 infection, which are referred to here as "sequelae of long COVID (LC)", are also a conspicuous global public health concern. Although such sequelae were well-documented, the understanding of and insights regarding LC-related sequelae remain inadequate due to the limitations of previous studies (the follow-up, methodological flaws, heterogeneity among studies, etc.). Notably, robust evidence regarding diagnosis and treatment of certain LC sequelae remain insufficient and has been a stumbling block to better management of these patients. This awkward situation motivated us to conduct this review. Here, we comprehensively reviewed the updated information, particularly focusing on clinical issues. We attempt to provide the latest information regarding LC-related sequelae by systematically reviewing the involvement of main organ systems. We also propose paths for future exploration based on available knowledge and the authors' clinical experience. We believe that these take-home messages will be helpful to gain insights into LC and ultimately benefit clinical practice in treating LC-related sequelae.
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Affiliation(s)
- Tetsuya Asakawa
- Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Qingxian Cai
- Department of Hepatology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jiayin Shen
- Department of Science and Education, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Ying Zhang
- Department of Endocrinology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Yongshuang Li
- Department of Dermatology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Peifen Chen
- Department of Respiratory Medicine, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Wen Luo
- Department of Respiratory Medicine, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jiangguo Zhang
- Department of Gastroenterology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jinfeng Zhou
- Department of Gastroenterology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Hui Zeng
- Department of Cardiology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Ruihui Weng
- Department of Neurology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Feng Hu
- Department of Nephrology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Huiquan Feng
- Department of Urology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jun Chen
- Department of Hepatology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jie Huang
- Department of Dermatology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Xiaoyin Zhang
- Department of Gastroenterology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Yu Zhao
- Department of Neurology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Liekui Fang
- Department of Urology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Rongqing Yang
- Department of Dermatology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Jia Huang
- Department of Intensive Care Unit, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Fuxiang Wang
- Department of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Yingxia Liu
- Department of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
| | - Hongzhou Lu
- Institute of Neurology, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China.,Department of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen, China
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28
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Carpenter KC, Yang J, Xu JJ. Animal Models for the Study of Neurologic Manifestations Of COVID-19. Comp Med 2023; 73:91-103. [PMID: 36744556 PMCID: PMC9948905 DOI: 10.30802/aalas-cm-22-000073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the worldwide coronavirus (COVID-19) pandemic, has infected an estimated 525 million people with over 6 million deaths. Although COVID-19 is primarily a respiratory disease, an escalating number of neurologic symptoms have been reported in humans. Some neurologic symptoms, such as loss of smell or taste, are mild. However, other symptoms, such as meningoencephalitis or stroke, are potentially fatal. Along with surveys and postmortem evaluations on humans, scientists worked with several animal species to try to elucidate the causes of neurologic symptoms. Neurologic sequelae remain challenging to study due to the complexity of the nervous system and difficulties in identification and quantification of neurologic signs. We reviewed animal models used in the study of neurologic COVID-19, specifically research in mice, hamsters, ferrets, and nonhuman primates. We summarized findings on the presence and pathologic effects of SARS-CoV-2 on the nervous system. Given the need to increase understanding of COVID-19 and its effects on the nervous system, scientists must strive to obtain new information from animals to reduce mortality and morbidity with neurologic complications in humans.
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Affiliation(s)
- Kelsey C Carpenter
- Division of Laboratory Animal Resources, Wayne State University, Detroit, Michigan;,
| | - Jibing Yang
- Center for Comparative Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jiajie J Xu
- Division of Animal Resources, University of Illinois at Urbana-Champaign, Champaign, Illinois
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29
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Ong IZ, Kolson DL, Schindler MK. Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC). Biomedicines 2023; 11:377. [PMID: 36830913 PMCID: PMC9953707 DOI: 10.3390/biomedicines11020377] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved. Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020-2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.
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Affiliation(s)
- Ian Z. Ong
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Dennis L. Kolson
- Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew K. Schindler
- Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA
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30
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Michael BD, Walton D, Westenberg E, García-Azorín D, Singh B, Tamborska AA, Netravathi M, Chomba M, Wood GK, Easton A, Siddiqi OK, Jackson TA, Pollak TA, Nicholson TR, Nair S, Breen G, Prasad K, Thakur KT, Chou SHY, Schmutzhard E, Frontera JA, Helbok R, Padovani A, Menon DK, Solomon T, Winkler AS. Consensus Clinical Guidance for Diagnosis and Management of Adult COVID-19 Encephalopathy Patients. J Neuropsychiatry Clin Neurosci 2023; 35:12-27. [PMID: 35872617 DOI: 10.1176/appi.neuropsych.22010002] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Encephalopathy, a common condition among patients hospitalized with COVID-19, can be a challenge to manage and negatively affect prognosis. While encephalopathy may present clinically as delirium, subsyndromal delirium, or coma and may be a result of systemic causes such as hypoxia, COVID-19 has also been associated with more prolonged encephalopathy due to less common but nevertheless severe complications, such as inflammation of the brain parenchyma (with or without cerebrovascular involvement), demyelination, or seizures, which may be disproportionate to COVID-19 severity and require specific management. Given the large number of patients hospitalized with severe acute respiratory syndrome coronavirus-2 infection, even these relatively unlikely complications are increasingly recognized and are particularly important because they require specific management. Therefore, the aim of this review is to provide pragmatic guidance on the management of COVID-19 encephalopathy through consensus agreement of the Global COVID-19 Neuro Research Coalition. A systematic literature search of MEDLINE, medRxiv, and bioRxiv was conducted between January 1, 2020, and June 21, 2021, with additional review of references cited within the identified bibliographies. A modified Delphi approach was then undertaken to develop recommendations, along with a parallel approach to score the strength of both the recommendations and the supporting evidence. This review presents analysis of contemporaneous evidence for the definition, epidemiology, and pathophysiology of COVID-19 encephalopathy and practical guidance for clinical assessment, investigation, and both acute and long-term management.
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Affiliation(s)
- Benedict D Michael
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Dean Walton
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Erica Westenberg
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - David García-Azorín
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Bhagteshwar Singh
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Arina A Tamborska
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - M Netravathi
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Mashina Chomba
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Greta K Wood
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Ava Easton
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Omar K Siddiqi
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Thomas A Jackson
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Thomas A Pollak
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Timothy R Nicholson
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Shalini Nair
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Gerome Breen
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Kameshwar Prasad
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Kiran T Thakur
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Sherry H-Y Chou
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Erich Schmutzhard
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Jennifer A Frontera
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Raimund Helbok
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Alessandro Padovani
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - David K Menon
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Tom Solomon
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
| | - Andrea S Winkler
- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
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- National Institute for Health and Care Research (NIHR) Health Protection Unit for Emerging and Zoonotic Infections, Liverpool, United Kingdom (Michael, Tamborska, Wood, Solomon); Department of Neurology, Walton Center National Health Service (NHS) Foundation Trust, Liverpool, United Kingdom (Michael, Walton, Tamborska, Wood, Solomon); Clinical Infection Microbiology and Immunology, Veterinary and Ecological Sciences, Institute for Infection, University of Liverpool, United Kingdom (Michael, Singh, Tamborska, Wood, Easton, Solomon); Department of Neurology, Center for Global Health, Faculty of Medicine, Technical University of Munich, Germany (Westenberg, Winkler); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (García-Azorín); Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital, United Kingdom (Singh); Department of Infectious Diseases, Christian Medical College, Vellore, India (Singh); National Institute of Mental Health and Neurosciences, Bangalore, India (Netravathi); Department of Medicine, Neurology Division, University Teaching Hospital, Lusaka, Zambia (Chomba, Siddiqi); Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York (Chomba, Thakur); Encephalitis Society, Malton, United Kingdom (Easton); Department of Neurology, Global Neurology Program, Beth Israel Deaconess Medical Center, Boston (Siddiqi); Department of Internal Medicine, Center for Vaccines and Virology Research, Beth Israel Deaconess Medical Center, Boston (Siddiqi); College of Medical and Dental Sciences, Institute of Inflammation and Aging, University of Birmingham, United Kingdom (Jackson); Department of Geriatric Medicine, University Hospitals Birmingham, United Kingdom (Jackson); Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Pollak); Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Nicholson, Breen); Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India (Nair); NIHR Maudsley Biomedical Research Center, South London and Maudsley NHS Trust and King's College London (Breen); Department of Neurology and Chief Executive Office, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India (Prasad); Departments of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh (Chou); Department of Neurology, Northwestern Feinberg School of Medicine, Chicago (Chou); Department of Neurology, Neurocritical Care Unit, Medical University Innsbruck, Austria (Schmutzhard, Helbok); New York University Grossman School of Medicine, New York (Frontera); Department of Clinical and Experimental Sciences, Institute of Neurology, University of Brescia, Italy (Padovani); Division of Anesthesia, University of Cambridge, United Kingdom (Menon); Faculty of Medicine, Center for Global Health, Institute of Health and Society, University of Oslo, Norway (Winkler)
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31
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Dunn E, Ibrahim F, Neme-Mercante S, Nair D, Morris S, Wang I, Punia V. Possible post-COVID epilepsy: A review of epilepsy monitoring unit admissions during the two years of COVID-19 pandemic. Epilepsy Behav Rep 2023; 21:100584. [PMID: 36685755 PMCID: PMC9847010 DOI: 10.1016/j.ebr.2023.100584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/07/2022] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Large scale healthcare data shows that new-onset epilepsy is noted in 0.3 % patients within 6 months of COVID-19 infection. We analyzed diagnostic epilepsy monitoring unit (EMU) evaluations to identify and report such cases. We thoroughly reviewed our EMU database and identified patients having "COVID" or "Corona" virus mention in their medical record from 03/15/2020 to 02/28/2022. Patients with epilepsy prior to COVID infection were excluded. Among 62 patients without prior epilepsy evaluated in the EMU for new-onset spells after confirmed COVID-19 infection, three patients were diagnosed with focal epilepsy. These three women without epilepsy risk factors had seizure onset at the time of, or within one to three months of, COVID-19 diagnosis. Their 3 T MRI imaging was non-lesional but revealed bilateral enlarged perivascular spaces. The video EEG monitoring was consistent with temporal or fronto-temporal lobe epilepsy in all three patients. Two of them developed drug-resistant epilepsy within six months of seizure onset. Our thorough analysis of diagnostic EMU evaluations during the two years of pandemic reveals three cases of post-COVID-19 epilepsy after non-symptomatic to mild disease. Although coincidental epilepsy onset cannot be ruled out, larger multicenter or national database investigations are needed to further analyze the possibility of post-COVID epilepsy.
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Affiliation(s)
- Eric Dunn
- Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Faisal Ibrahim
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Silvia Neme-Mercante
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Dileep Nair
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Spencer Morris
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Irene Wang
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vineet Punia
- Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
- Corresponding author at: 9500 Euclid Avenue, Cleveland, OH 44195 (Mail code S51), USA.
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32
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COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy. Signal Transduct Target Ther 2023; 8:24. [PMID: 36609561 PMCID: PMC9816522 DOI: 10.1038/s41392-022-01291-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 12/07/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023] Open
Abstract
Severe neurological symptoms are associated with Coronavirus disease 2019 (COVID-19). However, the morphologic features, pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection. In this study, neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining, ultrastructural examination under electron microscopy, and an image threshold method, in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals. Differentially expressed proteins were identified by quantitative proteomic assays. Histopathological findings included neurophagocytosis, microglia nodules, satellite phenomena, extensive edema, focal hemorrhage, and infarction, as well as infiltrating mononuclear cells. Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes, severe damage of the blood-brain barrier (BBB) and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+ monocytes and occasionally CD4+/CD8+ T lymphocytes. Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses, autophagy and cellular metabolism in COVID-19 patient brains compared with control brains. Proteins involved in brain development, neuroprotection, and extracellular matrix proteins of the basement membrane were downregulated, potentially caused by the activation of transforming growth factor β receptor and vascular endothelial growth factor signaling pathways. Thus, our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis (CAME) and suggest potential therapeutic targets.
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Karuppiah B, Chinniah R, Pandi S, Sevak V, Ravi PM, Thadakanathan D. Immunogenetic landscape of COVID-19 infections related neurological complications. COVID-19 IN ALZHEIMER'S DISEASE AND DEMENTIA 2023:133-146. [DOI: 10.1016/b978-0-443-15256-6.00009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
COVID-19 illness is associated with diverse neurological manifestations. Its exceptionally high prevalence results from unprecedented genetic diversity, genomic recombination, and superspreading. With each new mutation and variant, there are foreseeable risks of rising fatality and novel neurological motor complications in childhood and adult cases. This chapter provides an extensive review of COVID-19 neurological illness, notably the motor manifestations. Innovative treatments have been developed to stem the spread of infectious contagious illness, and attenuate the resultant cytokine storm and other postinfectious immune aspects responsible for postacute COVID-19 syndrome due to the multiplier effect of infection, immunity, and inflammation, termed I3.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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35
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Younger DS. Adult and childhood vasculitis. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:653-705. [PMID: 37562892 DOI: 10.1016/b978-0-323-98818-6.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability, making this a disorder of paramount importance to all clinicians. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary CNS and PNS vasculitides, predicated on achievement in primary systemic forms. Primary neurological vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, unfortunately without the benefit of RCTs, and tempered by the recognition of anticipated medication side effects. It may be said that efforts to define a disease are attempts to understand the very concept of the disease. This has been especially evident in systemic and neurological disorders associated with vasculitis. For the past 100 years, since the first description of granulomatous angiitis of the brain, the CNS vasculitides have captured the attention of generations of clinical investigators around the globe to reach a better understanding of vasculitides involving the central and peripheral nervous system. Since that time it has become increasingly evident that this will necessitate an international collaborative effort.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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36
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Alhazmi FH, Alsharif WM, Alshoabi SA, Gameraddin M, Aloufi KM, Abdulaal OM, Qurashi AA. Identifying cerebral microstructural changes in patients with COVID-19 using MRI: A systematic review. Brain Circ 2023; 9:6-15. [PMID: 37151797 PMCID: PMC10158661 DOI: 10.4103/bc.bc_77_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 12/05/2022] [Accepted: 12/13/2022] [Indexed: 05/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is an epidemic viral disease caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the excessive number of neurological articles that have investigated the effect of COVID-19 on the brain from the neurological point of view, very few studies have investigated the impact of COVID-19 on the cerebral microstructure and function of the brain. The aim of this study was to summarize the results of the existing studies on cerebral microstructural changes in COVID-19 patients, specifically the use of quantitative volumetric analysis, blood oxygen level dependent (BOLD), and diffusion tensor imaging (DTI). We searched PubMed/MEDLINE, ScienceDirect, Semantic Scholar, and Google Scholar from December 2020 to April 2022. A well-constructed search strategy was used to identify the articles for review. Seven research articles have met this study's inclusion and exclusion criteria, which have applied neuroimaging tools such as quantitative volumetric analysis, BOLD, and DTI to investigate cerebral microstructure changes in COVID-19 patients. A significant effect of COVID-19 was found in the brain such as hypoperfusion of cerebral blood flow, increased gray matter (GM) volume, and reduced cortical thickness. The insula and thalamic radiation were the most frequent GM region and white matter tract, respectively, that are involved in SARS-CoV-2. COVID-19 was found to be associated with changes in cerebral microstructures. These abnormalities in brain areas might lead to be associated with behaviors, mental and neurological alterations that need to be considered carefully in future studies.
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Affiliation(s)
- Fahad H. Alhazmi
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Walaa M. Alsharif
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Sultan Abdulwadoud Alshoabi
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Moawia Gameraddin
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
- Address for correspondence: Dr. Moawia Gameraddin, Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia. E-mail:
| | - Khalid M. Aloufi
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Osama M. Abdulaal
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Abdualziz A. Qurashi
- Department of Diagnostic Radiology Technology, Faculty of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
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Eschbacher KL, Larsen RA, Moyer AM, Majumdar R, Reichard RR. Neuropathological findings in COVID-19: an autopsy cohort. J Neuropathol Exp Neurol 2022; 82:21-28. [PMID: 36355625 DOI: 10.1093/jnen/nlac101] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The literature regarding the neuropathological findings in cases of SARS-CoV-2 infection, which causes coronavirus disease 2019 (COVID-19), is expanding. We identified 72 patients who died of COVID-19 (n = 48) or had recovered shortly before death (n = 24) and had autopsies performed at our institution (49 males, 23 females; median age at death 76.4 years, range: 0.0-95.0 years). Droplet digital polymerase chain reaction (ddPCR) for the detection of SARS-CoV-2 was performed (n = 58) in multiple brain regions. In cases the assay was successfully completed (n = 50), 98.0% were negative (n = 49) and 2% were indeterminate (n = 1). Most histologic findings were typical of the patient age demographic, such as neurodegenerative disease and arteriolosclerosis. A subset of cases demonstrated findings which may be associated with sequelae of critical illness. We identified 3 cases with destructive perivascular lesions with axonal injury, one of which also harbored perivascular demyelinating lesions. These rare cases may represent a parainfectious process versus sequelae of vascular injury. The lack of detectable SARS-CoV-2 by ddPCR or significant histologic evidence of direct infection suggests that active encephalitis is not a feature of COVID-19.
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Affiliation(s)
- Kathryn L Eschbacher
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rachel A Larsen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ann M Moyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ramanath Majumdar
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Robert Ross Reichard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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38
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Olumekor M, Stojić A, Kehler T, Polo F. The Impact of COVID-19 on the Quality of Life and Happiness of Care Home Residents in Croatia: A Cross-Sectional Study. Behav Sci (Basel) 2022; 12:463. [PMID: 36421759 PMCID: PMC9687193 DOI: 10.3390/bs12110463] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 09/08/2024] Open
Abstract
Care/nursing homes globally have been severely affected by the COVID-19 pandemic and have disproportionately experienced a high rate of mortality which led to the introduction of strict isolation policies. However, while there are studies on the mortality, epidemiology, staffing challenges, and mismanagement in long-term care homes as a result of COVID-19, there appears to be a paucity of information regarding the Quality of Life (QoL), happiness, and associated well-being of the elderly residents of these homes. Therefore, we examined if COVID-19 affected the happiness level, QoL, and financial condition of long-term care home residents in Croatia. To achieve this, a survey of 308 participants in eight long term care homes was conducted. Descriptive analysis was performed to describe the mean of all responses and the Bayesian Integrated Nested Laplace Approximation (INLA) was used to provide a detailed quantitative analysis of the results. We found that the QoL and happiness of residents remained relatively stable during the COVID-19 pandemic. However, the income level, financial outlook, marital status, and vaccination positivity influenced the QoL and happiness of care home residents to a considerable degree. We recommend that policy makers pay attention to these underlying factors.
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Affiliation(s)
- Michael Olumekor
- Graduate School of Economics and Management, Ural Federal University, 620014 Yekaterinburg, Russia
| | - Andrea Stojić
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Tatjana Kehler
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Francesco Polo
- Cultural Centre Humanitas in Conegliano, 31015 Treviso, Italy
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39
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Visvabharathy L, Hanson BA, Orban ZS, Lim PH, Palacio NM, Jimenez M, Clark JR, Graham EL, Liotta EM, Tachas G, Penaloza-MacMaster P, Koralnik IJ. T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2022:2021.08.08.21261763. [PMID: 34401886 PMCID: PMC8366804 DOI: 10.1101/2021.08.08.21261763] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Many people experiencing long COVID syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC), suffer from debilitating neurologic symptoms (Neuro-PASC). However, whether virus-specific adaptive immunity is affected in Neuro-PASC patients remains poorly understood. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated humoral and cellular responses toward SARS-CoV-2 Nucleocapsid protein at an average of 6 months post-infection compared to healthy COVID convalescents. Neuro-PASC patients also had enhanced virus-specific production of IL-6 from and diminished activation of CD8+ T cells. Furthermore, the severity of cognitive deficits or quality of life disturbances in Neuro-PASC patients were associated with a reduced diversity of effector molecule expression in T cells but elevated IFN-γ production to the C-terminal domain of Nucleocapsid protein. Proteomics analysis showed enhanced plasma immunoregulatory proteins and reduced pro-inflammatory and antiviral response proteins in Neuro-PASC patients compared with healthy COVID convalescents, which were also correlated with worse neurocognitive dysfunction. These data provide new insight into the pathogenesis of long COVID syndrome and a framework for the rational design of predictive biomarkers and therapeutic interventions.
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Affiliation(s)
- Lavanya Visvabharathy
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Barbara A. Hanson
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Zachary S. Orban
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Patrick H. Lim
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Nicole M. Palacio
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Millenia Jimenez
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Jeffrey R. Clark
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Edith L. Graham
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Eric M. Liotta
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - George Tachas
- Director, Drug Discovery & Patents, Antisense Therapeutics Ltd., Melbourne, Australia
| | - Pablo Penaloza-MacMaster
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
| | - Igor J. Koralnik
- Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago IL 60611 USA
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40
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Poloni TE, Moretti M, Medici V, Turturici E, Belli G, Cavriani E, Visonà SD, Rossi M, Fantini V, Ferrari RR, Carlos AF, Gagliardi S, Tronconi L, Guaita A, Ceroni M. COVID-19 Pathology in the Lung, Kidney, Heart and Brain: The Different Roles of T-Cells, Macrophages, and Microthrombosis. Cells 2022; 11:3124. [PMID: 36231087 PMCID: PMC9563269 DOI: 10.3390/cells11193124] [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: 08/26/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 12/03/2022] Open
Abstract
Here, we aim to describe COVID-19 pathology across different tissues to clarify the disease's pathophysiology. Lungs, kidneys, hearts, and brains from nine COVID-19 autopsies were compared by using antibodies against SARS-CoV-2, macrophages-microglia, T-lymphocytes, B-lymphocytes, and activated platelets. Alzheimer's Disease pathology was also assessed. PCR techniques were used to verify the presence of viral RNA. COVID-19 cases had a short clinical course (0-32 days) and their mean age was 77.4 y/o. Hypoxic changes and inflammatory infiltrates were present across all tissues. The lymphocytic component in the lungs and kidneys was predominant over that of other tissues (p < 0.001), with a significantly greater presence of T-lymphocytes in the lungs (p = 0.020), which showed the greatest presence of viral antigens. The heart showed scant SARS-CoV-2 traces in the endothelium-endocardium, foci of activated macrophages, and rare lymphocytes. The brain showed scarce SARS-CoV-2 traces, prominent microglial activation, and rare lymphocytes. The pons exhibited the highest microglial activation (p = 0.017). Microthrombosis was significantly higher in COVID-19 lungs (p = 0.023) compared with controls. The most characteristic pathological features of COVID-19 were an abundance of T-lymphocytes and microthrombosis in the lung and relevant microglial hyperactivation in the brainstem. This study suggests that the long-term sequelae of COVID-19 derive from persistent inflammation, rather than persistent viral replication.
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Affiliation(s)
- Tino Emanuele Poloni
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
- Department of Rehabilitation, ASP Golgi-Redaelli, Abbiategrasso, 20081 Milan, Italy
| | - Matteo Moretti
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Valentina Medici
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Elvira Turturici
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Giacomo Belli
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Elena Cavriani
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Silvia Damiana Visonà
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
| | - Michele Rossi
- Unit of Biostatistics, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Valentina Fantini
- Laboratory of Neurobiology and Neurogenetic, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Riccardo Rocco Ferrari
- Laboratory of Neurobiology and Neurogenetic, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Arenn Faye Carlos
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Stella Gagliardi
- Unit of Molecular Biology and Transcriptomics IRCCS Mondino Foundation, 27100 Pavia, Italy
| | - Livio Tronconi
- Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy
- Department of Forensic Medicine, IRCCS Mondino Foundation, 27100 Pavia, Italy
| | - Antonio Guaita
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
- Unit of Biostatistics, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
- Laboratory of Neurobiology and Neurogenetic, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
| | - Mauro Ceroni
- Department of Neurology and Neuropathology, Golgi-Cenci Foundation, Abbiategrasso, 20081 Milan, Italy
- Unit of Molecular Biology and Transcriptomics IRCCS Mondino Foundation, 27100 Pavia, Italy
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Saini A, Oh TH, Ghanem DA, Castro M, Butler M, Sin Fai Lam CC, Posporelis S, Lewis G, David AS, Rogers JP. Inflammatory and blood gas markers of COVID-19 delirium compared to non-COVID-19 delirium: a cross-sectional study. Aging Ment Health 2022; 26:2054-2061. [PMID: 34651536 DOI: 10.1080/13607863.2021.1989375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES We aimed to find the association of inflammation and respiratory failure with delirium in COVID-19 patients. We compare the inflammatory and arterial blood gas markers between patients with COVID-19 delirium and delirium in other medical disorders. METHODS This cross-sectional study used the CHART-DEL, a validated research tool, to screen patients for delirium retrospectively from clinical notes. Inflammatory markers C-reactive protein (CRP) and white cell count (WBC), and the partial pressures of oxygen (PO2) and carbon dioxide (PCO2) were compared between patients with COVID-19 delirium and delirium in other medical disorders. RESULTS In bivariate analysis, CRP (mg/L) was significantly higher in the COVID-19 group, (81.7 ± 80.0 vs. 58.8 ± 87.7, p = 0.04), and WBC (109/L) was significantly lower (7.44 ± 3.42 vs. 9.71 ± 5.45, p = 0.04). The geometric mean of CRP in the COVID-19 group was 140% higher in multiple linear regression (95% CI = 7-439%, p = 0.03) with age and sex as covariates. There were no significant differences in pO2 or pCO2 across groups. CONCLUSION The association between higher CRP and COVID-19 in patients with delirium may suggest an inflammatory basis for delirium in COVID-19. Our findings may assist clinicians in establishing whether delirium is due to COVID-19, which may improve management and outcomes of infected patients.
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Affiliation(s)
- Aman Saini
- Medical School, University College London, London, UK
| | - Tae Hyun Oh
- Department of Psychological Medicine, King's College London, London, UK
| | | | - Megan Castro
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Matthew Butler
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | | | - Sotiris Posporelis
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,South London and Maudsley NHS Foundation Trust, London, UK
| | - Glyn Lewis
- Division of Psychiatry, University College London, London, UK
| | - Anthony S David
- Institute of Mental Health, University College London, London, UK
| | - Jonathan P Rogers
- South London and Maudsley NHS Foundation Trust, London, UK.,Division of Psychiatry, University College London, London, UK
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da Silva Júnior RT, Santos Apolonio J, Cuzzuol BR, da Costa BT, Silva CS, Araújo GRL, Silva Luz M, Marques HS, Santos LKDS, Pinheiro SLR, Lima de Souza Gonçalves V, Calmon MS, Freire de Melo F. COVID-19 neuropsychiatric repercussions: Current evidence on the subject. World J Methodol 2022; 12:365-380. [PMID: 36186752 PMCID: PMC9516547 DOI: 10.5662/wjm.v12.i5.365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/30/2022] [Accepted: 07/25/2022] [Indexed: 02/07/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected the entire world, causing the coronavirus disease 2019 (COVID-19) pandemic since it was first discovered in Wuhan, China in December 2019. Among the clinical presentation of the disease, in addition to fever, fatigue, cough, dyspnea, diarrhea, nausea, vomiting, and abdominal pain, infected patients may also experience neurological and psychiatric repercussions during the course of the disease and as a post-COVID-19 sequelae. Thus, headache, dizziness, olfactory and gustatory dysfunction, cerebrovascular disorders, neuromuscular abnormalities, anxiety, depression, and post-traumatic stress disorder can occur both from the infection itself and from social distancing and quarantine. According to current evidence about this infection, the virus has the ability to infect the central nervous system (CNS) via angiotensin-converting enzyme 2 (ACE2) receptors on host cells. Several studies have shown the presence of ACE2 in nerve cells and nasal mucosa, as well as transmembrane serine protease 2, key points for interaction with the viral Spike glycoprotein and entry into the CNS, being olfactory tract and blood-brain barrier, through hematogenous dissemination, potential pathways. Thus, the presence of SARS-CoV-2 in the CNS supports the development of neuropsychiatric symptoms. The management of these manifestations seems more complex, given that the dense parenchyma and impermeability of brain tissue, despite protecting the brain from the infectious process, may hinder virus elimination. Still, some alternatives used in non-COVID-19 situations may lead to worse prognosis of acute respiratory syndrome, requiring caution. Therefore, the aim of this review is to bring more current points related to this infection in the CNS, as well as the repercussions of the isolation involved by the pandemic and to present perspectives on interventions in this scenario.
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Affiliation(s)
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Bruna Teixeira da Costa
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Hanna Santos Marques
- Universidade Estadual do Sudoeste da Bahia, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083900, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029094, Brazil
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Teo WP, Goodwill AM. Can exercise attenuate the negative effects of long COVID syndrome on brain health? Front Immunol 2022; 13:986950. [PMID: 36189287 PMCID: PMC9523009 DOI: 10.3389/fimmu.2022.986950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/31/2022] [Indexed: 11/28/2022] Open
Abstract
The impetus for many governments globally to treat the novel coronavirus (COVID-19) as an endemic warrant more research into the prevention, and management of long COVID syndrome (LCS). Whilst the data on LCS remains scarce, reports suggest a large proportion of recovered individuals will experience ongoing neuropsychological symptoms, even with mild disease severity. The pathophysiology underlying LCS is multifaceted. Evidence suggests that altered inflammatory, neurotrophic, and neurotransmitter pathways within the brain contribute to neuropsychological symptoms reported following COVID-19. Exercise or regular physical activity has long been shown to have positive effects on brain health and cognition through exerting positive effects on inflammatory markers, neurotransmitters, and neurotropic factors analogous to the neurophysiological pathways proposed to be disrupted by COVID-19 infection. Thus, exercise may serve as an important lifestyle behavior in the management of LCS. In this opinion article, we present the evidence to support the positive role of exercise in the management of cognitive symptom that manifest with LCS and discuss important considerations and interactions with cardiorespiratory and exercise tolerance complications that often present for individuals experiencing LCS. We highlight the need for more research and training of sports medicine practitioners and clinical exercise physiologists in the management of LCS with exercise and call for further research to understand the optimal dose-responses and exercise prescription guidelines for cognitive benefits and minimizing other complications.
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44
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Chen Y, Yang W, Chen F, Cui L. COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction. J Neuroinflammation 2022; 19:222. [PMID: 36071466 PMCID: PMC9450840 DOI: 10.1186/s12974-022-02579-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/24/2022] [Indexed: 11/10/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. Although COVID-19 was initially described as a respiratory disease, there is growing evidence that SARS-CoV-2 is able to invade the brains of COVID-19 patients and cause cognitive impairment. It has been reported that SARS-CoV-2 may have invasive effects on a variety of cranial nerves, including the olfactory, trigeminal, optic, and vagus nerves, and may spread to other brain regions via infected nerve endings, retrograde transport, and transsynaptic transmission. In addition, the blood-brain barrier (BBB), composed of neurovascular units (NVUs) lining the brain microvasculature, acts as a physical barrier between nerve cells and circulating cells of the immune system and is able to regulate the transfer of substances between the blood and brain parenchyma. Therefore, the BBB may be an important structure for the direct and indirect interaction of SARS-CoV-2 with the brain via the blood circulation. In this review, we assessed the potential involvement of neuroinvasion under the SARS-CoV-2 infection, and the potential impact of BBB disorder under SARS-CoV-2 infection on cognitive impairment.
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Affiliation(s)
- Yanting Chen
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, China
| | - Wenren Yang
- Department of Trauma Center, Hengyang Medical School, Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, China
| | - Feng Chen
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, China
| | - Lili Cui
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, China.
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Raviraj KG, Shobhana SS. Findings and inferences from full autopsies, minimally invasive autopsies and biopsy studies in patients who died as a result of COVID19 - A systematic review. Forensic Sci Med Pathol 2022; 18:369-381. [PMID: 35817946 PMCID: PMC9273702 DOI: 10.1007/s12024-022-00494-1] [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] [Accepted: 06/07/2022] [Indexed: 12/14/2022]
Abstract
Many articles on COVID19 deaths have been published since the pandemic has occurred. On reviewing the articles published until June 2021, the findings were very heterogeneous. Adding to the existing knowledge, there were also some unique observations made in the pathogenesis of COVID19. This review was done to determine the findings obtained and inferences drawn from various studies published globally among patients who died due to COVID19. PRISMA guidelines were used to conduct this systematic review. A search of databases like PubMed, ScienceDirect and Epistemonikos was done. The articles focusing on postmortem sample studies involving full autopsies, minimally invasive autopsies and tissue biopsy studies were screened and searched. The studies included were all the case reports, case series, narrative reviews and systematic reviews obtained in full text and in the English language containing study information, and samples obtained postmortem. The information obtained was tabulated using Microsoft excel sheets. The duplicates were removed at the beginning of the tabulation. Zotero referencing software was used for article sorting and citation and bibliography. Two authors independently reviewed the articles throughout the process to prevent bias. Adding to the heterogeneity of COVID19, the concept of lethality in preexisting disease conditions, the occurrence of secondary bacterial and fungal infections, and other pathogenetic mechanisms uniquely encountered are to be considered in treating the patients. Also, the presence of SARS-CoV-2 postmortem is established and should be considered a hazard.
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Affiliation(s)
- K. G. Raviraj
- Department of Forensic Medicine & Toxicology, East Point College of Medical Sciences and Research Center, Jnanaprabha Campus, Bidarahalli, Virgo Nagar Post, Bangalore, 560049 Karnataka India
| | - S. S. Shobhana
- Department of Forensic Medicine & Toxicology, St. Peter’s Medical College, Hospital and Research Institute, NH 44, Hosur, Tamil Nadu 635109 India
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46
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COVID-19, sens chimiques et pathologies métaboliques. MÉDECINE DES MALADIES MÉTABOLIQUES 2022. [PMCID: PMC9433342 DOI: 10.1016/j.mmm.2022.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Une réduction importante de l’odorat, indépendamment de l’obstruction nasale, et du goût, a été signalée comme un des symptômes majeurs suite à l’infection par la COVID-19. Cette réduction est si fréquente qu’elle a été proposée comme un des prédicteurs le plus relevant pour diagnostiquer l’infection. Différents mécanismes par lesquels les virus affectent l’odorat et le goût ont été proposés. L’ACE2 (enzyme de conversion de l’angiotensine 2) a été caractérisé comme le principal récepteur d’entrée du virus SARS-CoV-2 qui interagit avec les protéines « spikes » du virus, ce qui permet à ce dernier d’entrer dans la cellule hôte par un domaine de fusion. Il est principalement exprimé dans la partie supérieure des voies respiratoires, et la plus forte densité de ces protéines se trouve dans les épithéliums olfactif et gustatif. Les données actuellement disponibles indiquent que la cause la plus probable de l’anosmie pendant la COVID-19 est une altération de la fonction des neurones sensoriels olfactifs, associée à l’infection et à la mort des cellules microvillaires, et des péricytes vasculaires. Les mécanismes généraux sont les mêmes en ce qui concerne le goût. La pathogenèse des troubles olfactifs et gustatifs dans la COVID-19 peut entraîner des altérations diverses, dont des modifications de la prise alimentaire et du métabolisme énergétique. Les individus porteurs de pathologies métaboliques ayant une plus forte susceptibilité à la COVID-19 sont, de ce fait, plus exposés aux perturbations des sens chimiques et à leurs conséquences. De plus, des études récentes montrent que la COVID-19 augmenterait la susceptibilité au diabète en s’attaquant directement aux cellules β-pancréatiques.
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47
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Effects of Varying Glucose Concentrations on ACE2's Hypothalamic Expression and Its Potential Relation to COVID-19-Associated Neurological Dysfunction. Int J Mol Sci 2022; 23:ijms23179645. [PMID: 36077041 PMCID: PMC9455961 DOI: 10.3390/ijms23179645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/28/2022] [Accepted: 08/17/2022] [Indexed: 11/25/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has negatively impacted millions of lives, despite several vaccine interventions and strict precautionary measures. The main causative organism of this disease is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which infects the host via two key players: the angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2). Some reports revealed that patients with glycemic dysregulation could have increased susceptibility to developing COVID-19 and its related neurological complications. However, no previous studies have looked at the involvement of these key molecules within the hypothalamus, which is the central regulator of glucose in the brain. By exposing embryonic mouse hypothalamic neurons to varying glucose concentrations, we aimed to investigate the expression of ACE2 and TMPRSS2 using quantitative real time polymerase chain reaction and western blotting. A significant and time-dependent increase and decrease was observed on the viability of hypothalamic neurons with increasing and decreasing glucose concentrations, respectively (p < 0.01 and p < 0.001, respectively). Under the same increasing and decreasing glucose conditions, the expression of hypothalamic ACE2 also revealed a significant and time-dependent increase (p < 0.01). These findings suggest that SARS-CoV-2 invades the hypothalamic circuitry. In addition, it highlights the importance of strict glycemic control for COVID-19 in diabetic patients.
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48
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Serrano GE, Walker JE, Tremblay C, Piras IS, Huentelman MJ, Belden CM, Goldfarb D, Shprecher D, Atri A, Adler CH, Shill HA, Driver-Dunckley E, Mehta SH, Caselli R, Woodruff BK, Haarer CF, Ruhlen T, Torres M, Nguyen S, Schmitt D, Rapscak SZ, Bime C, Peters JL, Alevritis E, Arce RA, Glass MJ, Vargas D, Sue LI, Intorcia AJ, Nelson CM, Oliver J, Russell A, Suszczewicz KE, Borja CI, Cline MP, Hemmingsen SJ, Qiji S, Hobgood HM, Mizgerd JP, Sahoo MK, Zhang H, Solis D, Montine TJ, Berry GJ, Reiman EM, Röltgen K, Boyd SD, Pinsky BA, Zehnder JL, Talbot P, Desforges M, DeTure M, Dickson DW, Beach TG. SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19. J Neuropathol Exp Neurol 2022; 81:666-695. [PMID: 35818336 PMCID: PMC9278252 DOI: 10.1093/jnen/nlac056] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
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Affiliation(s)
- Geidy E Serrano
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Jessica E Walker
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Cécilia Tremblay
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA
| | | | - Danielle Goldfarb
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - David Shprecher
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Alireza Atri
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
- Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Charles H Adler
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Holly A Shill
- Barrow Neurological Institute, Phoenix, Arizona, USA
| | | | - Shyamal H Mehta
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Richard Caselli
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | - Bryan K Woodruff
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Thomas Ruhlen
- Banner Boswell Medical Center, Sun City, Arizona, USA
| | - Maria Torres
- Banner Boswell Medical Center, Sun City, Arizona, USA
| | - Steve Nguyen
- Banner Boswell Medical Center, Sun City, Arizona, USA
| | - Dasan Schmitt
- Banner Boswell Medical Center, Sun City, Arizona, USA
| | | | | | | | | | - Richard A Arce
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Michael J Glass
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Daisy Vargas
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Lucia I Sue
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | | | - Courtney M Nelson
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Javon Oliver
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Aryck Russell
- Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA (AR)
| | | | - Claryssa I Borja
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Madison P Cline
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | | | - Sanaria Qiji
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Holly M Hobgood
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
| | - Joseph P Mizgerd
- Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Malaya K Sahoo
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Haiyu Zhang
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Daniel Solis
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Thomas J Montine
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Gerald J Berry
- Department of Pathology, Stanford University, Stanford, California, USA
| | | | - Katharina Röltgen
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Scott D Boyd
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Benjamin A Pinsky
- Department of Pathology, Stanford University, Stanford, California, USA
- Division of Infectious Disease & Geographic Medicine, Department of Medicine, Stanford University, Stanford, California, USA
| | - James L Zehnder
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Pierre Talbot
- Laboratory of Neuroimmunology, Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Quebec, Canada
| | - Marc Desforges
- Mayo Clinic College of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA
- Laboratory of Virology, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Quebec, Canada
| | - Michael DeTure
- Département de microbiologie, infectiologie et Immunologie, Université de Montréal, Montréal, Quebec, Canada
| | - Dennis W Dickson
- Mayo Clinic College of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA
| | - Thomas G Beach
- From the Banner Sun Health Research Institute, Sun City, Arizona, USA
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Matschke J, Lahann H, Krasemann S, Altmeppen H, Pfefferle S, Galliciotti G, Fitzek A, Sperhake JP, Ondruschka B, Busch M, Rotermund N, Schulz K, Lohr C, Dottermusch M, Glatzel M. Young COVID-19 Patients Show a Higher Degree of Microglial Activation When Compared to Controls. Front Neurol 2022; 13:908081. [PMID: 35785352 PMCID: PMC9243237 DOI: 10.3389/fneur.2022.908081] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/20/2022] [Indexed: 11/20/2022] Open
Abstract
The severe acute respiratory syndrome-corona virus type 2 (SARS-CoV-2) is the cause of human coronavirus disease 2019 (COVID-19). Since its identification in late 2019 SARS-CoV-2 has spread rapidly around the world creating a global pandemic. Although considered mainly a respiratory disease, COVID-19 also encompasses a variety of neuropsychiatric symptoms. How infection with SARS-CoV-2 leads to brain damage has remained largely elusive so far. In particular, it has remained unclear, whether signs of immune cell and / or innate immune and reactive astrogliosis are due to direct effects of the virus or may be an expression of a non-specific reaction of the brain to a severe life-threatening disease with a considerable proportion of patients requiring intensive care and invasive ventilation activation. Therefore, we designed a case-control-study of ten patients who died of COVID-19 and ten age-matched non-COVID-19-controls to quantitatively assess microglial and astroglial response. To minimize possible effects of severe systemic inflammation and / or invasive therapeutic measures we included only patients without any clinical or pathomorphological indication of sepsis and who had not been subjected to invasive intensive care treatment. Our results show a significantly higher degree of microglia activation in younger COVID-19 patients, while the difference was less and not significant for older COVID-19 patients. The difference in the degree of reactive gliosis increased with age but was not influenced by COVID-19. These preliminary data warrants further investigation of larger patient cohorts using additional immunohistochemical markers for different microglial phenotypes.
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Affiliation(s)
- Jakob Matschke
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- *Correspondence: Jakob Matschke
| | - Henri Lahann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Susanne Krasemann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hermann Altmeppen
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Susanne Pfefferle
- Institute of Medical Microbiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Giovanna Galliciotti
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Antonia Fitzek
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan-Peter Sperhake
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benjamin Ondruschka
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Miriam Busch
- Institute of Cell and Systems Biology of Animals, University of Hamburg, Hamburg, Germany
| | - Natalie Rotermund
- Institute of Cell and Systems Biology of Animals, University of Hamburg, Hamburg, Germany
| | - Kristina Schulz
- Institute of Cell and Systems Biology of Animals, University of Hamburg, Hamburg, Germany
| | - Christian Lohr
- Institute of Cell and Systems Biology of Animals, University of Hamburg, Hamburg, Germany
| | - Matthias Dottermusch
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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50
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Hammoud H, Bendari A, Bendari T, Bougmiza I. Histopathological Findings in COVID-19 Cases: A Systematic Review. Cureus 2022; 14:e25573. [PMID: 35784976 PMCID: PMC9249248 DOI: 10.7759/cureus.25573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 11/05/2022] Open
Abstract
The ongoing coronavirus disease 2019 (COVID-19) pandemic has turned into one of the most serious public health crises of the last few decades. Although the disease can result in diverse and multiorgan pathologies, very few studies have addressed the postmortem pathological findings of COVID-19 cases. Active autopsy findings amid this pandemic could be an essential tool for diagnosis, surveillance, and research. We aimed to provide a comprehensive picture of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) histopathological features of different body organs through a systematic review of the published literature. A systematic search of electronic databases (PubMed, ScienceDirect, Google Scholar, medRxiv, and bioRxiv) for journal articles of different study designs reporting postmortem pathological findings in COVID-19 cases was performed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for conducting the review. A total of 50 articles reporting 430 cases were included in our analysis. Postmortem pathological findings were reported for different body organs: pulmonary system (42 articles), cardiovascular system (23 articles), hepatobiliary system (22 articles), kidney (16 articles), spleen and lymph nodes (12 articles), and central nervous system (seven articles). In lung samples, diffuse alveolar damage (DAD) was the most commonly reported finding in 239 cases (84.4%). Myocardial hypertrophy (87 cases, 51.2%), arteriosclerosis (121 cases, 62%), and steatosis (118 cases, 59.3%) were the most commonly reported pathological findings in the heart, kidney, and the hepatobiliary system respectively. Autopsy examination as an investigation tool could lead to a better understanding of SARS-CoV-2 pathophysiology, diagnosis, and management, subsequently improving patient care.
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Affiliation(s)
- Hamed Hammoud
- Preventive Medicine, Hamad Medical Corporation, Doha, QAT
| | - Ahmed Bendari
- Department of Pathology, Lenox Hill Hospital, New York, USA
| | | | - Iheb Bougmiza
- Community Medicine Residency Program, Primary Health Care Corporation, Doha, QAT
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