Cognitive and psychiatric symptom trajectories 2-3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK

Abstract

Background: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning.

Methods: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study.

Findings: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20).

Interpretation: Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19.

Funding: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.

Fig. 1. Distribution of the cognitive, psychiatric, and fatigue outcomes at 2-3 years post-COVID-19.

The colours encode the severity based on predefined thresholds. For fatigue, the scale is inverted (reporting 52-FACIT) to match the interpretation that worse outcomes appear on the right.

Fig. 2. Distribution of the normalised scores for the different cognitive subdomains tested.

The units represent the number of standard deviations below (negative) or above (positive) the mean for people with the same sociodemographic characteristics. For each domain, the mean score and its interquartile range (IQR) as well as the proportion of people with severe impairment (i.e. z-scores < -2) are provided. All distributions had mean significantly below zero (one-sample Wilcoxon test: p<0.0001).

Fig. 3

A-E Evolution of the proportion of participants with no, mild, moderate and severe burden of depression, anxiety, fatigue, and cognitive outcomes through follow-ups (among the same participants who provided data at different time points). For depression, anxiety, and fatigue, results of the paired t-tests are displayed in terms of the mean change in score and p-values (details, including confidence intervals can be found in the appendix p. 23). For fatigue, a negative change in FACIT means a worsening of symptoms, unlike for depression and anxiety. For objective and subjective cognitive outcomes, different scales were used at 2-3 years compared to 6 and 12 months and are therefore coloured differently. F Paired values of PHQ-9 at 6 months and 2-3 years. Graphs of paired values for GAD-7 and FACIT can be found in the appendix p. 20.

Fig. 4

A. Prevalence of severe psychiatric, cognitive and fatigue outcomes at 2-3 years as a function of recovery at 6 months, based on three predefined clusters of recovery (one per column). B Prediction of symptom burden at 2-3 years based on symptoms at 6 months. Each line connecting symptom X at 6-months to symptom Y at 2-3 years represents the proportion of variance in Y at 2-3 years explained by symptom X at 6 months when adjusting for Y at 6 months. Only predictions that were significant at p<0.05 are represented. For subjective cognitive decline and objective cognitive deficits, the instrument used at 6 months and 2-3 years differ which might have led to a lower proportion of variance explained. All coefficients, p-values and R² are provided in the appendix p. 26.