Neuropsychiatric and Cognitive Outcomes in Patients 6 Months After COVID-19 Requiring Hospitalization Compared With Matched Control Patients Hospitalized for Non-COVID-19 Illness

Abstract

Importance: Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking.

Objective: To investigate cognitive impairment, neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness.

Design, setting, and participants: This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset.

Exposures: Hospitalization for COVID-19.

Main outcomes and measures: Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing.

Results: A total of 85 COVID-19 survivors (36 [42%] women; mean [SD] age 56.8 [14] years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 [44%] women, mean age 59.4 years [SD, 13]) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing.

Conclusions and relevance: In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.

Figure 1.. Cognitive Assessment With Montreal Cognitive Assessment in COVID-19 Survivors and Matched Control Patients

A, Fully adjusted geometric mean MoCA score in 85 patients with COVID-19 and 60 control patients after hospitalization. Error bars indicate 95% CI. B, Geometric mean MoCA score of 15 patients with COVID-19 evaluated at discharge and follow-up. In total, 12 patients improved (8 with ≥5 points), 2 patients had no change and only 1 worsened, possibly owing to a minor left hemispheric stroke occurring a few weeks after discharge. C and D, Patients with and without COVID-19 stratified according to normal and abnormal findings of the MoCA based on a cutoff score of 26 or lower, respectively, and a MoCA cutoff score of 24 or less. The 2 groups were compared using Pearson χ²test.

Figure 2.. New-Onset Psychiatric International Classification of Diseases, 10th Revision (ICD-10) Diagnoses and Neuropsychiatric and Cognitive Symptoms in Survivors of COVID-19 and Matched Control Patients

Eighty-five patients with COVID-19 and 61 patients that did not have COVID-19 (control patients) were seen at approximately 6 months after COVID-19 symptom debut, for a face-to-face interview including the Mini International Neuropsychiatric Interview (MINI) and the Montreal Cognitive Assessment (MoCA). A, The frequencies of new-onset psychiatric diagnoses according to ICD-10, investigated via the MINI. “Psychiatric, any” and “anxiety, any” represent any new-onset psychiatric diagnosis and any new-onset anxiety diagnosis (panic attacks with or without agoraphobia, agoraphobia without panic attacks, and/or generalized anxiety), respectively. B, The frequencies of subjective neuropsychiatric and cognitive symptoms. After correction for multiple testing, the differences in new-onset generalized anxiety and altered sense of smell were no longer significant (P = .30 and P = .07, respectively). ^a Statistically significant difference (fully adjusted odds ratio [95% CI] = 0.13 [0.01-0.94]; P = .04). Adjusted P values for age, sex, intensive care unit admission, admission days, and days to follow-up. ^b Statistically significant difference (fully adjusted odds ratio [95% CI] = 4.56 [1.52-17.42]; P = .006). Adjusted P values for age, sex, intensive care unit admission, admission days, and days to follow-up.