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      Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 8 , 9 , 10 , 9 , 10 , 11 , 12 , 13 , 38 , 14 , 13 , 15 , 15 , 16 , 17 , 18 , 2 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 24 , 28 , 29 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 5 , 1 , 2 , 4 , 35 , 36 , 5 , 5 , 37 , , 2 ,
      Journal of Neurology
      Springer Berlin Heidelberg
      COVID-19, Biomarker, Prognosis, NfL

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          Abstract

          Background and aims

          To investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).

          Methods

          We conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.

          Results

          We identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13–3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively.

          Conclusions

          Blood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00415-023-11768-1.

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          Most cited references40

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host–Virus Interaction, and Proposed Neurotropic Mechanisms

            The recent outbreak of coronavirus infectious disease 2019 (COVID-19) has gripped the world with apprehension and has evoked a scare of epic proportion regarding its potential to spread and infect humans worldwide. As we are in the midst of an ongoing pandemic of COVID-19, scientists are struggling to understand how it resembles and differs from the severe acute respiratory syndrome coronavirus (SARS-CoV) at the genomic and transcriptomic level. In a short time following the outbreak, it has been shown that, similar to SARS-CoV, COVID-19 virus exploits the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry inside the cells. This finding raises the curiosity of investigating the expression of ACE2 in neurological tissue and determining the possible contribution of neurological tissue damage to the morbidity and mortality caused by COIVD-19. Here, we investigate the density of the expression levels of ACE2 in the CNS, the host–virus interaction and relate it to the pathogenesis and complications seen in the recent cases resulting from the COVID-19 outbreak. Also, we debate the need for a model for staging COVID-19 based on neurological tissue involvement.
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              The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients

              Abstract Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.
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                Author and article information

                Contributors
                mattfos89@gmail.com
                samir.aburumeileh@gmail.com
                Journal
                J Neurol
                J Neurol
                Journal of Neurology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-5354
                1432-1459
                15 May 2023
                : 1-14
                Affiliations
                [1 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Neurology, , University of California San Francisco (UCSF), ; San Francisco, USA
                [2 ]GRID grid.9018.0, ISNI 0000 0001 0679 2801, Department of Neurology, , Martin-Luther-University Halle-Wittenberg, ; Halle (Saale), Germany
                [3 ]GRID grid.414682.d, ISNI 0000 0004 1758 8744, Department of Neuroscience, , Neurology Unit, Maurizio Bufalini Hospital, AUSL Romagna, ; Cesena, Italy
                [4 ]GRID grid.410567.1, Department of Clinical Research, , University Hospital Basel and University of Basel, ; Basel, Switzerland
                [5 ]GRID grid.158820.6, ISNI 0000 0004 1757 2611, Department of Biotechnological and Applied Clinical Sciences, , University of L’Aquila, ; L’Aquila, Italy
                [6 ]GRID grid.413820.c, ISNI 0000 0001 2191 5195, Department of Stroke and Neuroscience, , Charing Cross Hospital, Imperial College London NHS Healthcare Trust, ; London, UK
                [7 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Brain Sciences, , Imperial College London, ; London SW7 2AZ, UK
                [8 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Neuroimmunological Diseases Section, , National Institute of Allergy and Infectious Diseases, National Institute of Health, ; Bethesda, MD USA
                [9 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Department of Neuroscience, , Mayo Clinic, ; Jacksonville, FL 32224 USA
                [10 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, ; Jacksonville, FL 32224 USA
                [11 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Department of Neurology, , Mayo Clinic, ; Jacksonville, FL 32224 USA
                [12 ]GRID grid.417467.7, ISNI 0000 0004 0443 9942, Division of Vascular and Endovascular Surgery, , Mayo Clinic, ; Jacksonville, FL 32224 USA
                [13 ]GRID grid.18887.3e, ISNI 0000000417581884, Institute of Experimental Neurology, Division of Neuroscience, , IRCCS Ospedale San Raffaele, ; Milan, Italy
                [14 ]GRID grid.18887.3e, ISNI 0000000417581884, Division of Immunology, Transplantation and Infectious Diseases, , IRCCS Ospedale San Raffaele, ; Milan, Italy
                [15 ]GRID grid.410567.1, Department of Acute Medical Care, Intensive Care Unit, , University Hospital Basel, ; Basel, Switzerland
                [16 ]GRID grid.410567.1, Department of Neurology, , University Hospital Basel and University of Basel, ; Basel, Switzerland
                [17 ]GRID grid.5611.3, ISNI 0000 0004 1763 1124, Neurology B, Department of Neurosciences, Biomedicine and Movement Sciences, , University of Verona, ; Verona, Italy
                [18 ]Department of Neurology, Landesklinikum Mistelbach-Gänserndorf, Mistelbach, Austria
                [19 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Neurology, , Oslo University Hospital, ; Oslo, Norway
                [20 ]GRID grid.470118.b, ISNI 0000 0004 0627 3835, Department of Internal Medicine, , Drammen Hospital, Vestre Viken Hospital Trust, ; Drammen, Norway
                [21 ]GRID grid.7914.b, ISNI 0000 0004 1936 7443, Department of Clinical Science, Faculty of Medicine, , University of Bergen, ; Bergen, Norway
                [22 ]GRID grid.5510.1, ISNI 0000 0004 1936 8921, Institute of Clinical Medicine, , University of Oslo, ; Oslo, Norway
                [23 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Infectious Diseases, , Oslo University Hospital, ; Oslo, Norway
                [24 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Medical Sciences, Neurology, , Uppsala University, ; Uppsala, Sweden
                [25 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Surgical Sciences, Radiology, , Uppsala University, ; Uppsala, Sweden
                [26 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Medical Sciences, , Uppsala University, ; Neurosurgery,, Sweden
                [27 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Neuroscience, , Karolinska Institute, ; Stockholm, Sweden
                [28 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, , Sahlgrenska Academy at the University of Gothenburg, ; Mölndal, Sweden
                [29 ]GRID grid.1649.a, ISNI 000000009445082X, Clinical Neurochemistry Laboratory, , Sahlgrenska University Hospital, ; Mölndal, Sweden
                [30 ]GRID grid.83440.3b, ISNI 0000000121901201, Department of Neurodegenerative Disease, , UCL Institute of Neurology, Queen Square, ; London, UK
                [31 ]GRID grid.83440.3b, ISNI 0000000121901201, UK Dementia Research Institute at UCL, ; London, UK
                [32 ]GRID grid.24515.37, ISNI 0000 0004 1937 1450, Hong Kong Center for Neurodegenerative Diseases, ; Clear Water Bay, Hong Kong, China
                [33 ]GRID grid.14003.36, ISNI 0000 0001 2167 3675, Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, , University of Wisconsin, University of Wisconsin-Madison, ; Madison, WI USA
                [34 ]GRID grid.410712.1, ISNI 0000 0004 0473 882X, Department of Neurology, , Ulm University Hospital, ; Ulm, Germany
                [35 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, , University Hospital and University of Basel, ; Basel, Switzerland
                [36 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, Multiple Sclerosis Centre, Department of Neurology, , University Hospital and University of Basel, ; Basel, Switzerland
                [37 ]Department of Neuroscience, Neurology Unit, S.Maria Delle Croci Hospital of Ravenna, AUSL Romagna, Ravenna, Italy
                [38 ]GRID grid.15496.3f, ISNI 0000 0001 0439 0892, Institute of Experimental Neurology, Division of Neuroscience, , Vita e Salute San Raffaele University, ; Milan, Italy
                Author information
                http://orcid.org/0000-0001-9731-4169
                http://orcid.org/0000-0003-4237-6850
                http://orcid.org/0000-0001-8009-8543
                http://orcid.org/0000-0001-6525-8174
                http://orcid.org/0000-0002-6794-3850
                http://orcid.org/0000-0002-4570-4533
                http://orcid.org/0000-0002-0959-9430
                http://orcid.org/0000-0002-4894-4858
                http://orcid.org/0000-0003-2959-129X
                http://orcid.org/0000-0002-4475-8142
                http://orcid.org/0000-0002-1571-6955
                http://orcid.org/0000-0001-7376-9425
                http://orcid.org/0000-0002-1281-7996
                http://orcid.org/0000-0002-6494-7776
                http://orcid.org/0000-0002-6575-356X
                http://orcid.org/0000-0002-8736-0070
                http://orcid.org/0000-0003-0358-9431
                http://orcid.org/0000-0001-8749-5533
                http://orcid.org/0000-0002-2824-2760
                http://orcid.org/0000-0002-1669-1032
                http://orcid.org/0000-0003-4009-4032
                http://orcid.org/0000-0001-9901-2949
                http://orcid.org/0000-0001-5615-2036
                http://orcid.org/0000-0003-1218-6247
                http://orcid.org/0000-0002-1952-8791
                http://orcid.org/0000-0002-1890-4193
                http://orcid.org/0000-0003-3930-4354
                http://orcid.org/0000-0002-1647-6201
                http://orcid.org/0000-0003-0651-1939
                http://orcid.org/0000-0001-9275-3066
                http://orcid.org/0000-0003-4273-4267
                http://orcid.org/0000-0002-6963-8892
                http://orcid.org/0000-0001-9501-4031
                http://orcid.org/0000-0002-0321-7155
                http://orcid.org/0000-0003-0631-8506
                Article
                11768
                10.1007/s00415-023-11768-1
                10183689
                37184659
                626d7921-4184-4201-b602-b0011547292c
                © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 1 April 2023
                : 4 May 2023
                : 5 May 2023
                Funding
                Funded by: NIH/NIDDS
                Award ID: 3R35NS097273-05S1
                Funded by: Oslo University Hospital, Research Council of Norway
                Award ID: 312780
                Funded by: Vivaldi Invest A/S owned by Jon Stephenson von Tetzchener,
                Funded by: Research Program of NIAD/NIH
                Funded by: Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”)
                Funded by: IRCCS Ospedale San Raffaele
                Funded by: FundRef http://dx.doi.org/10.13039/501100003196, Ministero della Salute;
                Funded by: Mrs. Luisella Carrozza Cassani (SDF)
                Categories
                Original Communication

                Neurology
                covid-19,biomarker,prognosis,nfl
                Neurology
                covid-19, biomarker, prognosis, nfl

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