Cited by 2,189Long-Term Effects of COVID-19COVID-19 Clinical Research StudiesCOVID-19 and Mental Health

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6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

Open access
Taquet, Maxime, Geddes, John R, Husain, Masud, Luciano, Sierra, Harrison, Paul J·2021·The Lancet Psychiatry

Published version of a preprint

Abstract

BACKGROUND: Neurological and psychiatric sequelae of COVID-19 have been reported, but more data are needed to adequately assess the effects of COVID-19 on brain health. We aimed to provide robust estimates of incidence rates and relative risks of neurological and psychiatric diagnoses in patients in the 6 months following a COVID-19 diagnosis. METHODS: For this retrospective cohort study and time-to-event analysis, we used data obtained from the TriNetX electronic health records network (with over 81 million patients). Our primary cohort comprised patients who had a COVID-19 diagnosis; one matched control cohort included patients diagnosed with influenza, and the other matched control cohort included patients diagnosed with any respiratory tract infection including influenza in the same period. Patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 were excluded from the control cohorts. All cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. We estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root, and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders (grouped and separately); substance use disorder; and insomnia. Using a Cox model, we compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory tract infections. We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders). We assessed the robustness of the differences in outcomes between cohorts by repeating the analysis in different scenarios. To provide benchmarking for the incidence and risk of neurological and psychiatric sequelae, we compared our primary cohort with four cohorts of patients diagnosed in the same period with additional index events: skin infection, urolithiasis, fracture of a large bone, and pulmonary embolism. FINDINGS: Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17-34·07), with 12·84% (12·36-13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78-48·09) and for a first diagnosis was 25·79% (23·50-28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50-0·63) for intracranial haemorrhage, 2·10% (1·97-2·23) for ischaemic stroke, 0·11% (0·08-0·14) for parkinsonism, 0·67% (0·59-0·75) for dementia, 17·39% (17·04-17·74) for anxiety disorder, and 1·40% (1·30-1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24-3·16) for intracranial haemorrhage, 6·92% (6·17-7·76) for ischaemic stroke, 0·26% (0·15-0·45) for parkinsonism, 1·74% (1·31-2·30) for dementia, 19·15% (17·90-20·48) for anxiety disorder, and 2·77% (2·31-3·33) for psychotic disorder. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio [HR] 1·44, 95% CI 1·40-1·47, for any diagnosis; 1·78, 1·68-1·89, for any first diagnosis) and those who had other respiratory tract infections (1·16, 1·14-1·17, for any diagnosis; 1·32, 1·27-1·36, for any first diagnosis). As with incidences, HRs were higher in patients who had more severe COVID-19 (eg, those admitted to ITU compared with those who were not: 1·58, 1·50-1·67, for any diagnosis; 2·87, 2·45-3·35, for any first diagnosis). Results were robust to various sensitivity analyses and benchmarking against the four additional index health events. INTERPRETATION: Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities. Complementary study designs, including prospective cohorts, are needed to corroborate and explain these findings. FUNDING: National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective cohort of 236,379 COVID-19 survivors, 33.62% received a neurological or psychiatric diagnosis within 6 months, and 12.84% received a first such diagnosis. Risks were higher than after influenza or other respiratory tract infections and were greatest in patients with more severe COVID-19, including ITU admission or encephalopathy.

Key findings

  • Among 236,379 patients with COVID-19, the estimated 6-month incidence of any neurological or psychiatric diagnosis was 33.62% (95% CI 33.17–34.07), and of any first diagnosis was 12.84% (12.36–13.33). For ITU-admitted patients, these were 46.42% (44.78–48.09) and 25.79% (23.50–28.25); for patients with encephalopathy, 62.34% (60.14–64.55) and 31.13% (27.29–35.36).
  • Individual 6-month incidences in the whole COVID-19 cohort included anxiety disorder 17.39% (17.04–17.74), mood disorder 13.66% (13.35–13.99), psychotic disorder 1.40% (1.30–1.51), ischaemic stroke 2.10% (1.97–2.23), intracranial haemorrhage 0.56% (0.50–0.63), dementia 0.67% (0.59–0.75), and parkinsonism 0.11% (0.08–0.14).
  • Compared with influenza, COVID-19 was associated with higher risk of any diagnosis (HR 1.44, 95% CI 1.40–1.47) and any first diagnosis (1.78, 1.68–1.89); compared with other respiratory tract infections, HRs were 1.16 (1.14–1.17) and 1.32 (1.27–1.36), respectively. ITU admission versus no ITU admission was associated with HR 1.58 (1.50–1.67) for any diagnosis and 2.87 (2.45–3.35) for any first diagnosis.
  • Most diagnostic categories were more common after COVID-19 than after influenza, except parkinsonism and Guillain-Barré syndrome, for which HRs were not significantly greater than 1 versus influenza.

Methods

  • Retrospective cohort and time-to-event analysis using the TriNetX electronic health records network (over 81 million patients, 62 health-care organisations, primarily USA). The primary cohort had confirmed COVID-19 (ICD-10 U07.1); control cohorts had influenza or any respiratory tract infection including influenza, with COVID-19/SARS-CoV-2-positive patients excluded. All cohorts included patients older than 10 years with an index event on or after Jan 20, 2020, alive on Dec 13, 2020.
  • Fourteen neurological and psychiatric outcomes were assessed 1–180 days after the index event, with first versus any diagnoses estimated depending on whether outcomes were chronic or recurrent. Cohorts were propensity-score matched 1:1 on 55 variables; incidence was estimated with Kaplan-Meier, comparisons with log-rank tests, and hazard ratios with Cox proportional hazards models.
  • Secondary analyses examined COVID-19 severity via hospitalisation, ITU admission, and encephalopathy, with matched comparisons; sensitivity analyses included patients who died, test-confirmed COVID-19, and pre-pandemic influenza comparisons, plus benchmarking against four additional index events.

Limitations

  • The paper states limitations inherent to electronic health records: unknown completeness of records, no validation of diagnoses, and sparse information on socioeconomic and lifestyle factors. It also notes that the choice of comparator cohort influenced hazard ratio magnitude, that encephalopathy was likely under-recorded and results should not be generalised to all patients with delirium, that timing differences and undiagnosed COVID-19 in controls likely made HRs underestimates, and that the study can only show associations, not causality.
  • Evident from the text: despite propensity-score matching, residual confounding may remain; diagnoses rely on ICD-10 codes; and follow-up is limited to 6 months, so longer-term trajectories and duration of risk are not established.

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Integrity signals

Registry

Crossref · 10.1016/s2215-0366(21)00084-5

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Figure 1 Kaplan-Meier estimates for the incidence of major outcomes after COVID-19 compared with other RTIs Shaded areas are 95% CIs. For incidences of first diagnoses, the number in brackets corresponds to all patients who did not have the outcome before the follow-up period. For diagnostic subcategories, see appendix (pp 8–10). RTI=respiratory tract infection.
Figure 1 Kaplan-Meier estimates for the incidence of major outcomes after COVID-19 compared with other RTIs Shaded areas are 95% CIs. For incidences of first diagnoses, the number in brackets corresponds to all patients who did not have the outcome before the follow-up period. For diagnostic subcategories, see appendix (pp 8–10). RTI=respiratory tract infection.CC BY · PubMed Central
Figure 2 Kaplan-Meier estimates for the incidence of major outcomes after COVID-19 comparing patients requiring hospitalisation with matched patients not requiring hospitalisation, and comparing those who had encephalopathy with matched patients who did not have encephalopathy 95% CIs are omitted for clarity but are shown in the appendix (p 23). For incidences of first diagnoses, the total number corresponds to all patients who did not have the outcome before the follow-up period. The equivalent figure showing the comparison between patients with intensive therapy unit admission versus those without is presented in the appendix (p 22).
Figure 2 Kaplan-Meier estimates for the incidence of major outcomes after COVID-19 comparing patients requiring hospitalisation with matched patients not requiring hospitalisation, and comparing those who had encephalopathy with matched patients who did not have encephalopathy 95% CIs are omitted for clarity but are shown in the appendix (p 23). For incidences of first diagnoses, the total number corresponds to all patients who did not have the outcome before the follow-up period. The equivalent figure showing the comparison between patients with intensive therapy unit admission versus those without is presented in the appendix (p 22).CC BY · PubMed Central

Verification

Claims the paper makes

61 Own result · 12 Own interpretation · 8 Not checked yet · 8 Own method · 1 No basis given

Verify all 10 references — free account

Show all 58 claims

  • It may state two separate claims as one. 24
  • Probably not a substantial claim. 10
32 of 32
  • The paper relies on this without support.

    Diagnoses recorded in the TriNetX electronic health records accurately reflect the neurological and psychiatric outcomes under study.

    “Available data include demographics, diagnoses (using codes from ICD-10), medications, procedures, and measurements (eg, blood pressure and body-mass index).”
  • The paper relies on this without support.

    The ICD-10 code U07.1 reliably identifies patients with COVID-19.

    “The primary cohort was defined as all patients who had a confirmed diagnosis of COVID-19 (ICD-10 code U07.1).”
  • The paper relies on this without support.

    Propensity score matching on the measured covariates adequately controls for confounding by unmeasured factors.

    “We used propensity score matching19 to create cohorts with matched baseline characteristics, done within the TriNetX network.”
  • The authors state this as an assumption.

    Hospitalisation, ITU admission, and encephalopathy are valid proxies for COVID-19 severity.

    “We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders).”
  • The paper relies on this without support.

    Diagnoses recorded in the electronic health records accurately reflect patients' true clinical diagnoses.

    “Nevertheless, they have weaknesses inherent to an electronic health records study,29 such as the unknown completeness of records, no validation of diagnoses, and sparse information on socioeconomic and lifestyle factors.”
  • The paper relies on this without support.

    The propensity score matching adequately controls for confounding by measured covariates.

    “even after extensive propensity score matching for other factors (eg, age or previous cerebrovascular disease)”
  • The paper relies on this without support.

    The comparator cohorts (influenza and other respiratory tract infections) are appropriate to estimate the excess risk attributable to COVID-19.

    “the choice of cohorts against which to compare COVID-19 outcomes influenced the magnitude of the HRs (table 3, appendix p 34).”
  • The paper relies on this without support.

    The 6-month follow-up period is sufficient to capture the main neurological and psychiatric outcomes of interest.

    “Longer-term studies are needed to ascertain the duration of risk and the trajectory for individual diagnoses.”
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Metadata

Authors
Taquet, M., Geddes, J. R., Husain, M., Luciano, S., & Harrison, P. J.
Affiliations
  • Oxford Health NHS Foundation Trust (GB)
  • TriNetX (United States) (US)
Corresponding author
Harrison, Paul J
Venue
The Lancet Psychiatry
Publisher
Elsevier BV
Published
2021-05
Volume
8
Issue
5
Pages
416-427
ISSN
2215-0366 (ISSN-L)
OpenAlex
W3148333766
Cited by
2,189
References
35
Citations by year
2026: 137 · 2025: 186 · 2024: 346 · 2023: 467 · 2022: 640 · 2021: 408
FWCI
222.72
Type
journal article
Language
en
Open access
Locations
  • The Lancet Psychiatry (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
NIHR
Topics
  • Health Sciences › Medicine › Clinical Neurology › Long-Term Effects of COVID-19
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Social Sciences › Psychology › Clinical Psychology › COVID-19 and Mental Health
Keywords
COVID-19 pandemic, neurological sequelae, psychiatric sequelae, long COVID, incidence, respiratory infections, stroke, dementia, psychosis, anxiety disorders, substance use disorders, insomnia, Guillain-Barré syndrome, parkinsonism, encephalitis, delirium, COVID-19 severity, hospitalization, intensive care unit admission
MeSH terms
COVID-19, SARS-CoV-2, Mental Disorders, Female, Humans, Influenza, Human, Male, Middle Aged, Nervous System Diseases, Outcome and Process Assessment, Health Care, Research Design, Respiratory Tract Infections, Risk Factors, Severity of Illness Index, Global Health, Cohort Studies, Incidence, Proportional Hazards Models, Risk Assessment, Electronic Health Records

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