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

Felicia Ceban, Susan Ling, Leanna M W Lui, Yena Lee, Hartej Gill, Kayla M Teopiz, Nelson B Rodrigues, Mehala Subramaniapillai, Joshua D Di Vincenzo, Bing Cao, Kangguang Lin, Rodrigo B Mansur, Roger C Ho, Joshua D Rosenblat, Kamilla W Miskowiak, Maj Vinberg, Vladimir Maletic, Roger S McIntyre, Felicia Ceban, Susan Ling, Leanna M W Lui, Yena Lee, Hartej Gill, Kayla M Teopiz, Nelson B Rodrigues, Mehala Subramaniapillai, Joshua D Di Vincenzo, Bing Cao, Kangguang Lin, Rodrigo B Mansur, Roger C Ho, Joshua D Rosenblat, Kamilla W Miskowiak, Maj Vinberg, Vladimir Maletic, Roger S McIntyre

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.

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.

Copyright © 2022 Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Flow diagram of study selection.
Fig. 2
Fig. 2
Pooled proportions of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis.
Fig. 3
Fig. 3
Pooled proportions of individuals exhibiting cognitive impairment 12 or more weeks following COVID-19 diagnosis.

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