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Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome

Published online by Cambridge University Press:  04 April 2024

Aristo Vojdani ,
Abbas F. Almulla Open the ORCID record for Abbas F. Almulla [Opens in a new window] ,
Bo Zhou ,
Hussein K. Al-Hakeim Open the ORCID record for Hussein K. Al-Hakeim [Opens in a new window]  and
Michael Maes Open the ORCID record for Michael Maes [Opens in a new window]
Aristo Vojdani
Affiliation:
Immunosciences Lab, Inc., Los Angeles, CA 90035, USA Cyrex Laboratories, LLC, Phoenix, AZ 85034, USA
Abbas F. Almulla
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
Bo Zhou
Affiliation:
Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China
Hussein K. Al-Hakeim
Affiliation:
Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq
Michael Maes*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria Research Center, Medical University of Plovdiv, Plovdiv, Bulgaria Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
*
Corresponding author: M. Maes; Email: dr.michaelmaes@hotmail.com
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Abstract

Background:

Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID.

Objectives:

To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers.

Methods:

We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5′-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR).

Results:

Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709).

Conclusion:

Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

Keywords

Affective disorderschronic fatigue syndromedepressionlong COVIDneuroimmuneoxidative stress
Type
Original Article
Information
Acta Neuropsychiatrica , First View , pp. 1 - 13
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Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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Footnotes

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These authors are contributed equally.

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