The Lancet Psychiatry
Published: April 06, 2021
DOI: https://doi.org/10.1016/S2215-0366(21)00084-5
Raw Data: https://osf.io/7tzvy/wiki/home/
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.
AUTHORS: Maxime Taquet, PhD, Prof John R Geddes, MD, Prof Masud Husain, FRCP, Sierra Luciano, BA, Prof Paul J Harrison, FRCPsych
Summary
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.
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Evidence before this study We searched Web of Science and Medline on Aug 1 and Dec 31, 2020, for studies in English, with the terms “(COVID-19 OR SARS-CoV2 OR SARS-CoV-2) AND (psychiatri* or neurologi*) AND (incidence OR epidemiologi* OR ‘systematic review’ or ‘meta-analysis’)”. We found case series and reviews of series reporting neurological and neuropsychiatric disorders during acute COVID-19 illness. We found one large electronic health records study of the psychiatric sequelae in the 3 months after a COVID-19 diagnosis. It reported an increased risk for anxiety and mood disorders and dementia after COVID-19 compared with a range of other health events; the study also reported the incidence of each disorder. We are not aware of any large-scale data regarding the incidence or relative risks of neurological diagnoses in patients who had recovered from COVID-19.
Added value of this study To our knowledge, we provide the first meaningful estimates of the risks of major neurological and psychiatric conditions in the 6 months after a COVID-19 diagnosis, using the electronic health records of over 236 000 patients with COVID-19. We report their incidence and hazard ratios compared with patients who had had influenza or other respiratory tract infections. We show that both incidence and hazard ratios were greater in patients who required hospitalisation or admission to the intensive therapy unit (ITU), and in those who had encephalopathy (delirium and other altered mental states) during the illness compared with those who did not.
Implications of all the available evidence COVID-19 was robustly associated with an increased risk of neurological and psychiatric disorders in the 6 months after a diagnosis. Given the size of the pandemic and the chronicity of many of the diagnoses and their consequences (eg, dementia, stroke, and intracranial haemorrhage), substantial effects on health and social care systems are likely to occur. Our data provide important evidence indicating the scale and nature of services that might be required. The findings also highlight the need for enhanced neurological follow-up of patients who were admitted to ITU or had encephalopathy during their COVID-19 illness.
Introduction
Since the COVID-19 pandemic began on March 11, 2020, there has been concern that survivors might be at an increased risk of neurological disorders. This concern, initially based on findings from other coronaviruses,1 was followed rapidly by case series,2, 3, 4 emerging evidence of COVID-19 CNS involvement,5, 6, 7 and the identification of mechanisms by which this could occur.8, 9, 10, 11 Similar concerns have been raised regarding psychiatric sequelae of COVID-19,12, 13 with evidence showing that survivors are indeed at increased risk of mood and anxiety disorders in the 3 months after infection.14 However, we need large scale, robust, and longer term data to properly identify and quantify the consequences of the COVID-19 pandemic on brain health. Such information is required both to plan services and identify research priorities.
In this study, we used an electronic health records network to investigate the incidence of neurological and psychiatric diagnoses in survivors in the 6 months after documented clinical COVID-19 infection, and we compared the associated risks with those following other health conditions. We explored whether the severity of COVID-19 infection, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy, affects these risks. We also assessed the trajectory of hazard ratios (HRs) across the 6-month period.
Methods
Study design and data collection
For this retrospective cohort study, we used The TriNetX Analytics Network, a federated network recording anonymised data from electronic health records in 62 health-care organisations, primarily in the USA, comprising 81 million patients. Available data include demographics, diagnoses (using codes from ICD-10), medications, procedures, and measurements (eg, blood pressure and body-mass index). The health-care organisations are a mixture of hospitals, primary care, and specialist providers, contributing data from uninsured and insured patients. These organisations warrant that they have all necessary rights, consents, approvals, and authority to provide the data to TriNetX, so long as their name remains anonymous as a data source and their data are used for research purposes. By use of the TriNetX user interface, cohorts can be created on the basis of inclusion and exclusion criteria, matched for confounding variables with a built-in propensity score-matching algorithm, and compared for outcomes of interest over specified time periods. Additional details about TriNetX, its data, provenance, and functionalities, are presented in the appendix (pp 1–2).
Cohorts
The primary cohort was defined as all patients who had a confirmed diagnosis of COVID-19 (ICD-10 code U07.1). We also constructed two matched control cohorts: patients diagnosed with influenza (ICD-10 codes J09–11) and patients diagnosed with any respiratory tract infection including influenza (ICD-10 codes J00–06, J09–18, or J20–22). We excluded patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 from the control cohorts. We refer to the diagnosis of COVID-19 (in the primary cohort) and influenza or other respiratory tract infections (in the control cohorts) as index events. The cohorts included all patients older than 10 years who had an index event on or after Jan 20, 2020 (the date of the first recorded COVID-19 case in the USA), and who were still alive at the time of the main analysis (Dec 13, 2020). Additional details on cohorts are provided in the appendix (pp 2–3).
Covariates
We used a set of established and suspected risk factors for COVID-19 and for more severe COVID-19 illness:15, 16 age, sex, race, ethnicity, obesity, hypertension, diabetes, chronic kidney disease, asthma, chronic lower respiratory diseases, nicotine dependence, substance use disorder, ischaemic heart disease and other forms of heart disease, socioeconomic deprivation, cancer (and haematological cancer in particular), chronic liver disease, stroke, dementia, organ transplant, rheumatoid arthritis, lupus, psoriasis, and disorders involving an immune mechanism. To capture these risk factors in patients' health records, we used 55 variables. More details, including ICD-10 codes, are provided in the appendix (pp 3–4). Cohorts were matched for all these variables, as described in the following subsections.
We estimated the diagnostic incidence of the neurological and psychiatric outcomes of the primary cohort in the 6 months after a COVID-19 diagnosis. In the whole cohort, 33·62% (95% CI 33·17–34·07) of patients received a diagnosis (table 2). For the cohort subgroups, these estimates were 38·73% (37·87–39·60) for patients who were hospitalised, 46·42% (44·78–48·09) for those admitted to ITU, and 62·34% (60·14–64·55) for those diagnosed with encephalopathy. A similar, but more marked, increasing trend was observed for patients receiving their first recorded neurological or psychiatric diagnosis (table 2). Results according to sex, race, and age are shown in the appendix (p 28). The baseline characteristics of the COVID-19 cohort divided into those who did versus those who did not have a neurological or psychiatric outcome are also shown in the appendix (p 7).
Various adverse neurological and psychiatric outcomes occurring after COVID-19 have been predicted and reported.1, 2, 3, 4, 5, 14 The data presented in this study, from a large electronic health records network, support these predictions and provide estimates of the incidence and risk of these outcomes in patients who had COVID-19 compared with matched cohorts of patients with other health conditions occurring contemporaneously with the COVID-19 pandemic (Table 2, Table 3, figure 1).
The severity of COVID-19 had a clear effect on subsequent neurological diagnoses (Table 4, Table 5, figure 2). Overall, COVID-19 was associated with increased risk of neurological and psychiatric outcomes, but the incidences and HRs of these were greater in patients who had required hospitalisation, and markedly so in those who had required ITU admission or had developed encephalopathy, even after extensive propensity score matching for other factors (eg, age or previous cerebrovascular disease). Potential mechanisms for this association include viral invasion of the CNS,10, 11 hypercoagulable states,22 and neural effects of the immune response.9 However, the incidence and relative risk of neurological and psychiatric diagnoses were also increased even in patients with COVID-19 who did not require hospitalisation.
Some specific neurological diagnoses merit individual mention. Consistent with several other reports,23, 24 the risk of cerebrovascular events (ischaemic stroke and intracranial haemorrhage) was elevated after COVID-19, with the incidence of ischaemic stroke rising to almost one in ten (or three in 100 for a first stroke) in patients with encephalopathy. A similarly increased risk of stroke in patients who had COVID-19 compared with those who had influenza has been reported.25 Our previous study reported preliminary evidence for an association between COVID-19 and dementia.14 The data in this study support this association. Although the estimated incidence was modest in the whole COVID-19 cohort (table 2), 2·66% of patients older than 65 years (appendix p 28) and 4·72% who had encephalopathy (table 2), received a first diagnosis of dementia within 6 months of having COVID-19. The associations between COVID-19 and cerebrovascular and neurodegenerative diagnoses are concerning, and information about the severity and subsequent course of these diseases is required.
Whether COVID-19 is associated with Guillain-Barré syndrome remains unclear;26 our data were also equivocal, with HRs increased with COVID-19 compared with other respiratory tract infections but not with influenza (table 3), and increased compared with three of the four other index health events (appendix p 34). Concerns have also been raised about post-COVID-19 parkinsonian syndromes, driven by the encephalitis lethargica epidemic that followed the 1918 influenza pandemic.27 Our data provide some support for this possibility, although the incidence was low and not all HRs were significant. Parkinsonism might be a delayed outcome, in which case a clearer signal might emerge with a longer follow-up.
The findings regarding anxiety and mood disorders were broadly consistent with 3-month outcome data from a study done in a smaller number of cases than our cohort, using the same network,14 and showed that the HR remained elevated, although decreasing, at the 6-month period. Unlike the earlier study, and in line with previous suggestions,28 we also observed a significantly increased risk of psychotic disorders, probably reflecting the larger sample size and longer duration of follow-up reported here. Substance use disorders and insomnia were also more common in COVID-19 survivors than in those who had influenza or other respiratory tract infections (except for the incidence of a first diagnosis of substance use disorder after COVID-19 compared with other respiratory tract infections). Therefore, as with the neurological outcomes, the psychiatric sequelae of COVID-19 appear widespread and to persist up to, and probably beyond, 6 months. Compared with neurological disorders, common psychiatric disorders (mood and anxiety disorders) showed a weaker relationship with the markers of COVID-19 severity in terms of incidence (table 2) or HRs (table 5). This might indicate that their occurrence reflects, at least partly, the psychological and other implications of a COVID-19 diagnosis rather than being a direct manifestation of the illness.
HRs for most neurological outcomes were constant, and hence the risks associated with COVID-19 persisted up to the 6-month timepoint. Longer-term studies are needed to ascertain the duration of risk and the trajectory for individual diagnoses.
Rs for most neurological outcomes were constant, and hence the risks associated with COVID-19 persisted up to the 6-month timepoint. Longer-term studies are needed to ascertain the duration of risk and the trajectory for individual diagnoses.
Our findings are robust given the sample size, the propensity score matching, and the results of the sensitivity and secondary analyses. 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. These issues primarily affect the incidence estimates, but the choice of cohorts against which to compare COVID-19 outcomes influenced the magnitude of the HRs (table 3, appendix p 34). The analyses regarding encephalopathy (delirium and related conditions) deserve a note of caution. Even among patients who were hospitalised, only about 11% received this diagnosis, whereas much higher rates would be expected.18, 30 Under-recording of delirium during acute illness is well known and probably means that the diagnosed cases had prominent or sustained features; as such, results for this group should not be generalised to all patients with COVID-19 who experience delirium. We also note that encephalopathy is not just a severity marker but a diagnosis in itself, which might predispose to, or be an early sign of, other neuropsychiatric or neurodegenerative outcomes observed during follow-up. The timing of index events was such that most infections with influenza and many of the other respiratory tract infections occurred earlier on during the pandemic, whereas the incidence of COVID-19 diagnoses increased over time (appendix p 24). The effect of these timing differences on observed rates of sequelae is unclear but, if anything, they are likely to make the HRs an underestimate because COVID-19 cases were diagnosed at a time when all other diagnoses were made at a lower rate in the population (appendix p 24). Some patients in the comparison cohorts are likely to have had undiagnosed COVID-19; this would also tend to make our HRs an underestimate. Finally, a study of this kind can only show associations; efforts to identify mechanisms and assess causality will require prospective cohort studies and additional study designs.
In summary, the present data show that COVID-19 is followed by significant rates of neurological and psychiatric diagnoses over the subsequent 6 months. Services need to be configured, and resourced, to deal with this anticipated need.
Contributors
PJH and MT were granted unrestricted access to the TriNetX Analytics network for the purposes of research, and with no constraints on the analyses done or the decision to publish; they designed the study and directly accessed the TriNetX Analytics web interface to do it. MT, JRG, MH, and PJH defined cohort inclusion and exclusion criteria, and the outcome criteria and analytical approaches. MT did the data analyses, assisted by SL and PJH. All authors contributed to data interpretation. MT and PJH wrote the paper with input from JRG, MH, and SL. MT and PJH verified the data. PJH is the guarantor. PJH and MT had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication.
Data sharing
The TriNetX system returned the results of these analyses as .csv files, which were downloaded and archived. Data presented in this paper can be freely accessed online. Additionally, TriNetX will grant access to researchers if they have a specific concern (through a third-party agreement option).
Declaration of interests
SL is an employee of TriNetX. All other authors declare no competing interests.
Acknowledgments
This work was supported by the NIHR Oxford Health Biomedical Research Centre ( grant BRC-1215–20005 ). MT is an NIHR Academic Clinical Fellow. MH is supported by a Wellcome Trust Principal Research Fellowship and the NIHR Oxford Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the UK National Health Service, NIHR, or the UK Department of Health.