Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

doi:10.1016/j.bbi.2021.12.020

Meta-Analysis

. 2022 Mar:101:93-135.

doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29.

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

Felicia Ceban¹, Susan Ling², Leanna M W Lui³, Yena Lee⁴, Hartej Gill³, Kayla M Teopiz³, Nelson B Rodrigues³, Mehala Subramaniapillai³, Joshua D Di Vincenzo², Bing Cao⁵, Kangguang Lin⁶, Rodrigo B Mansur⁷, Roger C Ho⁸, Joshua D Rosenblat⁹, Kamilla W Miskowiak¹⁰, Maj Vinberg¹¹, Vladimir Maletic¹², Roger S McIntyre¹³

Affiliations

¹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.
² Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
⁴ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Braxia Health, Mississauga, ON, Canada.
⁵ Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing 400715, China.
⁶ Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University, (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China; Laboratory of Emotion and Cognition, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China.
⁷ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁸ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.
⁹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Psychology, University of Copenhagen, Copenhagen, Denmark; Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Copenhagen, Denmark.
¹¹ Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Psychiatric Research Unit, Psychiatric Centre North Zealand, Hillerød, Denmark.
¹² Department of Psychiatry, University of South Carolina, Greenville, SC, USA.
¹³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Braxia Health, Mississauga, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: Roger.McIntyre@uhn.ca.

PMID: 34973396
PMCID: PMC8715665
DOI: 10.1016/j.bbi.2021.12.020

Meta-Analysis

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

Felicia Ceban et al. Brain Behav Immun. 2022 Mar.

. 2022 Mar:101:93-135.

doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29.

Authors

Affiliations

¹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.
² Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
⁴ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Braxia Health, Mississauga, ON, Canada.
⁵ Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing 400715, China.
⁶ Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University, (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China; Laboratory of Emotion and Cognition, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China.
⁷ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁸ Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.
⁹ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Psychology, University of Copenhagen, Copenhagen, Denmark; Mental Health Services, Capital Region of Denmark, Copenhagen University Hospital, Copenhagen, Denmark.
¹¹ Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Psychiatric Research Unit, Psychiatric Centre North Zealand, Hillerød, Denmark.
¹² Department of Psychiatry, University of South Carolina, Greenville, SC, USA.
¹³ Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Braxia Health, Mississauga, ON, Canada; Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: Roger.McIntyre@uhn.ca.

PMID: 34973396
PMCID: PMC8715665
DOI: 10.1016/j.bbi.2021.12.020

Abstract

Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome.

Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome.

Data sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists.

Study selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected.

Data extraction & synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model.

Main outcomes & measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome.

Results: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I² = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I² = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals.

Conclusions & relevance: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena.

Study registration: PROSPERO (CRD42021256965).

Keywords: Anhedonia; Bipolar; Brain; Brain fog; COVID-19; Cognition; Cognitive impairment; Depression; Fatigue; Functional outcomes; Immunology; Inflammation; Long COVID; Mental illness; Population health; Post-COVID-19 condition; Post-COVID-19 syndrome.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Fig. 1**
Flow diagram of study selection.

**Fig. 2**
Pooled proportions of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis.

**Fig. 3**
Pooled proportions of individuals exhibiting cognitive impairment 12 or more weeks following COVID-19 diagnosis.

See this image and copyright information in PMC

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References

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1. Tenforde M.W., Kim S.S., Lindsell C.J., Billig Rose E., Shapiro N.I., Files D.C., Gibbs K.W., Erickson H.L., Steingrub J.S., Smithline H.A., Gong M.N., Aboodi M.S., Exline M.C., Henning D.J., Wilson J.G., Khan A., Qadir N., Brown S.M., Peltan I.D., Rice T.W., Hager D.N., Ginde A.A., Stubblefield W.B., Patel M.M., Self W.H., Feldstein L.R., Hart K.W., McClellan R., Dorough L., Dzuris N., Griggs E.P., Kassem A.M., Marcet P.L., Ogokeh C.E., Sciarratta C.N., Siddula A., Smith E.R., Wu M.J. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network - United States, march-June 2020. MMWR Morb. Mortal. Wkly Rep. 2020;69(30):993–998. doi: 10.15585/mmwr.mm6930e1. - DOI - PMC - PubMed

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[1] 1. Coronavirus disease (COVID-19) – World Health Organization. Accessed June 27, 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

[2] 1. Coronavirus disease (COVID-19) – World Health Organization. Accessed June 27, 2021. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

[3] Wu S.L., Mertens A.N., Crider Y.S., Nguyen A., Pokpongkiat N.N., Djajadi S., Seth A., Hsiang M.S., Colford J.M., Reingold A., Arnold B.F., Hubbard A., Benjamin-Chung J. Substantial underestimation of SARS-CoV-2 infection in the United States. Nat. Commun. 2020;11(1) doi: 10.1038/s41467-020-18272-4. - DOI - PMC - PubMed

[4] Wu S.L., Mertens A.N., Crider Y.S., Nguyen A., Pokpongkiat N.N., Djajadi S., Seth A., Hsiang M.S., Colford J.M., Reingold A., Arnold B.F., Hubbard A., Benjamin-Chung J. Substantial underestimation of SARS-CoV-2 infection in the United States. Nat. Commun. 2020;11(1) doi: 10.1038/s41467-020-18272-4. - DOI - PMC - PubMed

[5] Havers F.P., Reed C., Lim T., Montgomery J.M., Klena J.D., Hall A.J., Fry A.M., Cannon D.L., Chiang C.-F., Gibbons A., Krapiunaya I., Morales-Betoulle M., Roguski K., Rasheed M.A.U., Freeman B., Lester S., Mills L., Carroll D.S., Owen S.M., Johnson J.A., Semenova V., Blackmore C., Blog D., Chai S.J., Dunn A., Hand J., Jain S., Lindquist S., Lynfield R., Pritchard S., Sokol T., Sosa L., Turabelidze G., Watkins S.M., Wiesman J., Williams R.W., Yendell S., Schiffer J., Thornburg N.J. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-may 12, 2020. JAMA Intern Med. 2020;180(12):1576. doi: 10.1001/jamainternmed.2020.4130. - DOI - PubMed

[6] Havers F.P., Reed C., Lim T., Montgomery J.M., Klena J.D., Hall A.J., Fry A.M., Cannon D.L., Chiang C.-F., Gibbons A., Krapiunaya I., Morales-Betoulle M., Roguski K., Rasheed M.A.U., Freeman B., Lester S., Mills L., Carroll D.S., Owen S.M., Johnson J.A., Semenova V., Blackmore C., Blog D., Chai S.J., Dunn A., Hand J., Jain S., Lindquist S., Lynfield R., Pritchard S., Sokol T., Sosa L., Turabelidze G., Watkins S.M., Wiesman J., Williams R.W., Yendell S., Schiffer J., Thornburg N.J. Seroprevalence of antibodies to SARS-CoV-2 in 10 sites in the United States, March 23-may 12, 2020. JAMA Intern Med. 2020;180(12):1576. doi: 10.1001/jamainternmed.2020.4130. - DOI - PubMed

[7] Aizenman N. Why the pandemic is 10 times worse than you think. NPR. https://www.npr.org/sections/health-shots/2021/02/06/964527835/why-the-p.... Published February 6, 2021. Accessed May 19, 2021.

[8] Aizenman N. Why the pandemic is 10 times worse than you think. NPR. https://www.npr.org/sections/health-shots/2021/02/06/964527835/why-the-p.... Published February 6, 2021. Accessed May 19, 2021.

[9] Tenforde M.W., Kim S.S., Lindsell C.J., Billig Rose E., Shapiro N.I., Files D.C., Gibbs K.W., Erickson H.L., Steingrub J.S., Smithline H.A., Gong M.N., Aboodi M.S., Exline M.C., Henning D.J., Wilson J.G., Khan A., Qadir N., Brown S.M., Peltan I.D., Rice T.W., Hager D.N., Ginde A.A., Stubblefield W.B., Patel M.M., Self W.H., Feldstein L.R., Hart K.W., McClellan R., Dorough L., Dzuris N., Griggs E.P., Kassem A.M., Marcet P.L., Ogokeh C.E., Sciarratta C.N., Siddula A., Smith E.R., Wu M.J. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network - United States, march-June 2020. MMWR Morb. Mortal. Wkly Rep. 2020;69(30):993–998. doi: 10.15585/mmwr.mm6930e1. - DOI - PMC - PubMed

[10] Tenforde M.W., Kim S.S., Lindsell C.J., Billig Rose E., Shapiro N.I., Files D.C., Gibbs K.W., Erickson H.L., Steingrub J.S., Smithline H.A., Gong M.N., Aboodi M.S., Exline M.C., Henning D.J., Wilson J.G., Khan A., Qadir N., Brown S.M., Peltan I.D., Rice T.W., Hager D.N., Ginde A.A., Stubblefield W.B., Patel M.M., Self W.H., Feldstein L.R., Hart K.W., McClellan R., Dorough L., Dzuris N., Griggs E.P., Kassem A.M., Marcet P.L., Ogokeh C.E., Sciarratta C.N., Siddula A., Smith E.R., Wu M.J. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network - United States, march-June 2020. MMWR Morb. Mortal. Wkly Rep. 2020;69(30):993–998. doi: 10.15585/mmwr.mm6930e1. - DOI - PMC - PubMed

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Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

Affiliations

Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis

Authors

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Abstract

Conflict of interest statement

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