Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study

Tim J Hartung; Thomas Bahmer; Irina Chaplinskaya-Sobol; Jürgen Deckert; Matthias Endres; Katrin Franzpötter; Johanna Geritz; Karl G Haeusler; Grit Hein; Peter U Heuschmann; Sina M Hopff; Anna Horn; Thomas Keil; Michael Krawczak; Lilian Krist; Wolfgang Lieb; Corina Maetzler; Felipe A Montellano; Caroline Morbach; Christian Neumann; Carolin Nürnberger; Anne-Kathrin Russ; Lena Schmidbauer; Sein Schmidt; Stefan Schreiber; Flo Steigerwald; Stefan Störk; Thomas Zoller; Walter Maetzler; Carsten Finke; NAPKON Study Group

doi:10.1016/j.eclinm.2024.102456

Predictors of non-recovery from fatigue and cognitive deficits after COVID-19: a prospective, longitudinal, population-based study

EClinicalMedicine. 2024 Feb 3:69:102456. doi: 10.1016/j.eclinm.2024.102456. eCollection 2024 Mar.

Authors

Tim J Hartung¹, Thomas Bahmer^{2

3}, Irina Chaplinskaya-Sobol⁴, Jürgen Deckert⁵, Matthias Endres^{1

6

7

8

9}, Katrin Franzpötter¹⁰, Johanna Geritz¹¹, Karl G Haeusler¹², Grit Hein⁵, Peter U Heuschmann^{12

13

14

15}, Sina M Hopff¹⁶, Anna Horn^{13

14}, Thomas Keil¹⁷, Michael Krawczak¹⁸, Lilian Krist¹⁷, Wolfgang Lieb¹⁰, Corina Maetzler¹¹, Felipe A Montellano^{13

19

20}, Caroline Morbach²¹, Christian Neumann¹¹, Carolin Nürnberger^{13

14}, Anne-Kathrin Russ¹⁸, Lena Schmidbauer^{13

14}, Sein Schmidt²², Stefan Schreiber², Flo Steigerwald¹, Stefan Störk^{19

23}, Thomas Zoller²⁴, Walter Maetzler¹¹, Carsten Finke¹; NAPKON Study Group

Affiliations

¹ Charité - Universitätsmedizin Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany.
² Internal Medicine Department I, University Hospital Schleswig Holstein, Campus Kiel, Germany.
³ Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany.
⁴ Department of Medical Informatics, University Medical Center Göttingen, Germany.
⁵ Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie, Uniklinik Würzburg, Germany.
⁶ Center for Stroke Research Berlin, Berlin, Germany.
⁷ ExcellenceCluster NeuroCure, Berlin, Germany.
⁸ German Center for Neurodegenerative Diseases (DZNE), Partner Site Berlin, Germany.
⁹ German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany.
¹⁰ Institute of Epidemiology, Kiel University, Germany.
¹¹ Neurology Department, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
¹² Department of Neurology, Universitätsklinikum Würzburg, Würzburg, Germany.
¹³ University of Würzburg, Institute of Clinical Epidemiology and Biometry, Würzburg, Germany.
¹⁴ University Hospital Würzburg, Institute for Medical Data Science, Würzburg, Germany.
¹⁵ University Hospital Würzburg, Clinical Trial Center, Würzburg, Germany.
¹⁶ University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Germany.
¹⁷ Charité - Universitätsmedizin Berlin, Institute of Social Medicine, Epidemiology and Health Economics, Berlin, Germany.
¹⁸ Institute of Medical Informatics and Statistics, Kiel University, University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany.
¹⁹ University Hospital Würzburg, Department Clinical Research and Epidemiology, Comprehensive Heart Failure Center, Würzburg, Germany.
²⁰ Germany University Hospital Würzburg, Department of Neurology, Würzburg, Germany.
²¹ University Hospital Würzburg, Department for Medicine I and Comprehensive Heart Failure Center, Germany.
²² Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Clinical Study Center, Germany.
²³ Department of Internal Medicine I, University Hospital Würzburg, Germany.
²⁴ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases, Respiratory and Critical Care Medicine, Berlin, Germany.

Abstract

Background: Despite the high prevalence and major disability associated with fatigue and cognitive deficits after SARS-CoV-2 infection, little is known about long-term trajectories of these sequelae. We aimed to assess long-term trajectories of these conditions and to identify risk factors for non-recovery.

Methods: We analyzed longitudinal data from the population-based COVIDOM/NAPKON-POP cohort in Germany. Participants with confirmed SARS-CoV-2 infection were assessed at least 6 months (baseline) and again at least 18 months (follow-up) after infection using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale (cutoff ≤ 30) and the Montreal Cognitive Assessment (MoCA, cutoff ≤ 25). Predictors of recovery from fatigue or cognitive deficits between assessments were identified through univariate and multivariable logistic regression models. The COVIDOM study is registered at the German registry for clinical studies (DRKS00023742) and at ClinicalTrials.gov (NCT04679584).

Findings: Between 15 November 2020 and 9 May 2023, a total of 3038 participants were assessed at baseline (median 9 months after infection) and 83% responded to invitations for follow-up (median 26 months after infection). At baseline, 21% (95% confidence interval (CI) [20%, 23%]) had fatigue and 23% (95% CI [22%, 25%]) had cognitive deficits according to cutoff scores on the FACIT-Fatigue or MoCA. Participants with clinically relevant fatigue (at baseline) showed significant improvement in fatigue scores at follow-up (Hedges' g [95% CI] = 0.73 [0.60, 0.87]) and 46% (95% CI [41%, 50%]) had recovered from fatigue. Participants with cognitive deficits showed a significant improvement in cognitive scores (g [95% CI] = 1.12 [0.90, 1.33]) and 57% (95% CI [50%, 64%]) had recovered from cognitive deficits. Patients with fatigue exhibiting a higher depressive symptom burden and/or headache at baseline were significantly less likely to recover. Significant risk factors for cognitive non-recovery were male sex, older age and <12 years of school education. Importantly, SARS-CoV-2 reinfection had no significant impact on recovery from fatigue or cognitive deficits.

Interpretation: Fatigue and cognitive deficits are common sequelae after SARS-CoV-2 infection. These syndromes improved over time and about half of the patients recovered within two years. The identified risk factors for non-recovery from fatigue and cognitive deficits could play an important role in shaping targeted strategies for treatment and prevention.

Funding: Funded by the German Federal Ministry of Education and Research (BMBF; grant number 01KX2121) and German Research Foundation (DFG) Excellence Cluster "Position Medicine in Information".

Keywords: COVID-19; Cognitive dysfunction; Fatigue; Longitudinal studies; Post-acute COVID-19 syndrome.

Associated data

ClinicalTrials.gov/NCT04679584