Summary
Background
COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear.
Methods
In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age <18 years [children], 18–64 years [adults], and ≥65 years [older adults]) and date of diagnosis. We assessed the risks of 14 neurological and psychiatric diagnoses after SARS-CoV-2 infection and compared these risks with the matched comparator cohort. The 2-year risk trajectories were represented by time-varying hazard ratios (HRs) and summarised using the 6-month constant HRs (representing the risks in the earlier phase of follow-up, which have not yet been well characterised in children), the risk horizon for each outcome (ie, the time at which the HR returns to 1), and the time to equal incidence in the two cohorts. We also estimated how many people died after a neurological or psychiatric diagnosis during follow-up in each age group. Finally, we compared matched cohorts of patients diagnosed with COVID-19 directly before and after the emergence of the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529) variants.
Findings
We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42·5 years [SD 21·9]; 741 806 [57·8%] were female and 542 192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar.
Interpretation
This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them.
Funding
National Institute for Health and Care Research Oxford Health Biomedical Research Centre, The Wolfson Foundation, and MQ Mental Health Research.
Introduction
- Rogers JP
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- et al.
,
- Taquet M
- Luciano S
- Geddes JR
- Harrison PJ
,
,
- Taquet M
- Geddes JR
- Husain M
- Luciano S
- Harrison PJ
,
- Daugherty SE
- Guo Y
- Heath K
- et al.
However, more than 2 years after the first case was diagnosed, three important questions remain unanswered.
,
- Taquet M
- Geddes JR
- Husain M
- Luciano S
- Harrison PJ
,
- Daugherty SE
- Guo Y
- Heath K
- et al.
,
One study estimated the prevalence of self-reported anxiety, depressive, and sleep symptoms at 2, 2–6, and 6–16 months after COVID-19 diagnosis and found that the prevalence of depressive symptoms, but not sleep symptoms, decreased over time.
- Magnúsdóttir I
- Lovik A
- Unnarsdóttir AB
- et al.
Although informative, the self-reported nature of these findings and the restricted range of outcomes measured limit their usefulness for clinical practice and for informing public health policies.
Research in contextEvidence before this studyWe searched PubMed (Medline) on March 21, 2022, for publications since database inception in English using the terms “(neuropsychiatr*[Title/Abstract] OR neurologic*[Title/Abstract] OR psychiatric[Title/Abstract] OR depress*[Title/Abstract] OR anxiety*[Title/Abstract] OR cognit*[Title/Abstract] OR brain[Title/Abstract]) AND (variant*[Title/Abstract] OR omicron[Title/Abstract] OR delta[Title/Abstract] OR evolution[Title/Abstract]) AND (COVID[Title/Abstract] OR COVID-19[Title/Abstract] OR SARS*[Title/Abstract])”. We found cohort studies and systematic reviews reporting neuropsychiatric sequelae persisting up to 10 months after COVID-19. We found one large, 6-month electronic health records study of neuropsychiatric disorders after a COVID-19 diagnosis. This study reported increased incidence and relative risk of cognitive symptoms and anxiety or depression 6 months after COVID-19, compared with influenza. We are not aware of any large-scale data regarding long-term COVID-19 sequelae beyond 12 months, or the evolution of incidence or relative risk of neuropsychiatric diagnoses in patients recovered from COVID-19 throughout the pandemic, stratified by COVID-19 variant or vaccination status.Added value of this studyTo our knowledge, this is the first study with a comparator cohort that assesses the risks of a range of neurological and psychiatric outcomes of COVID-19 up to 2 years after the index SARS-CoV-2 infection. We found that the risks of post-COVID neurological and psychiatric outcomes follow different trajectories: the risk of cognitive deficit, dementia, psychotic disorder, and epilepsy or seizures remain elevated 2 years after SARS-CoV-2 infection, while the risks of other diagnoses (notably, mood and anxiety disorders) subside after 1–2 months and show no overall excess over the whole 2-year follow-up. We also found that risk trajectories differ somewhat in children: they are not at an increased risk of mood or anxiety disorders (even over the first 6 months) and their risk of cognitive deficit is transient, but they share adults’ risk of several other diagnoses and are notably at risk of epilepsy or seizures. Finally, we found that the risks of neurological and psychiatric outcomes remain similar after the emergence of the omicron (B.1.1.529) variant as with the delta (B.1.617.2) variant, but are offset by a significantly lower death rate.Implications of all the available evidenceThe persisting increased risk of post-COVID-19 cognitive deficit, dementia, psychotic disorders, and epilepsy or seizures 2 years after the index infection calls for enhanced service provision to diagnose and manage these sequelae, and research to understand the mechanisms. The differing profile of post-COVID-19 neurological and psychiatric diagnoses in children informs the risk–benefit association of policies aimed at preventing COVID-19 in paediatric populations and suggests that underlying mechanisms might in part be different from those in adults. The observation of comparable neurological and psychiatric risks just after (compared with just before) emergence of the omicron variant suggests an ongoing neuropsychiatric burden of COVID-19 even with variants that lead to otherwise less severe disease.
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- Gloy V
- et al.
Neurological manifestations of COVID-19 in paediatric populations (aged
- Ray STJ
- Abdel-Mannan O
- Sa M
- et al.
but only one controlled study has investigated the risk of neurological and psychiatric outcomes after SARS-CoV-2 infection.
- Roessler M
- Tesch F
- Batram M
- et al.
This study was limited to a 3-month follow-up period and measured neurological and psychiatric outcomes as two broad categories, without reporting the risk of individual diagnoses.
- Wang L
- Berger NA
- Kaelber DC
- Davis PB
- Volkow ND
- Xu R
,
- Maslo C
- Friedland R
- Toubkin M
- Laubscher A
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,
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- Ferguson NM
- Nash SG
- et al.
and a different symptom profile,
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also leads to fewer neurological and psychiatric sequelae.
We used electronic health records to investigate these three questions. We assessed the 2-year risk trajectories of 14 neurological and psychiatric diagnoses in three age groups (children younger than 18 years, adults aged 18–64 years, and older adults aged ≥65 years), and if and when these risks returned to baseline. Then we compared these risks between patients diagnosed just after versus just before the emergence of the alpha, delta, and omicron variants.
Results
Table 1Baseline characteristics for the whole COVID-19 cohort and the matched cohorts of COVID-19 patients and patients diagnosed with another respiratory infection
Figure 1Kaplan-Meier curves and time-varying HRs over the 2-year follow-up period for each outcome (A-N) and any first outcome (O) after COVID-19 or another respiratory infection in the propensity-score matched cohorts
Table 2Risk of neurological and psychiatric sequelae at 6 months, risk horizon, and time to equal incidence for each diagnosis after COVID-19 versus after other respiratory infections, in the propensity-score matched population
The risk horizon is the time at which the time-varying hazard ratio returns to 1 (ie, the baseline risk in the comparison cohort). The time to equal incidence is the time at which the cumulative incidences of the two cohorts become equal. The risk horizon and time to equal incidence are only included for outcomes with a significantly increased hazard ratio at 6 months; for outcomes that did not reach the risk horizon or time to equal incidence within the follow-up period (up to 730 days), they are shown as not reached (NR).
Figure 2Hazard ratios for the 6-month risk of neurological and psychiatric sequelae after COVID-19 versus another respiratory infection, in different age groups, in the propensity-score matched population
Data are hazard ratios with 95% CIs. Children defined as younger than 18 years, adult, aged 18–64 years, and older adults as aged 65 years or older
Figure 3Cumulative incidence of neurological and psychiatric diagnoses at 2 years after COVID-19 versus another respiratory infection, in different age groups, by mortality status at 2 years (or censorship date), in the matched cohorts
Figure 4Risk of neurological and psychiatric outcomes after versus before the emergence of different SARS-CoV-2 variants, in the USA
Discussion
,
- Taquet M
- Geddes JR
- Husain M
- Luciano S
- Harrison PJ
,
- Daugherty SE
- Guo Y
- Heath K
- et al.
we found substantial differences in the trajectories of these risks within the first 2 years after diagnosis. We also found that risk profiles and trajectories vary in children compared with adults and older adults, and differ between variants of SARS-CoV-2.
We summarised risk trajectories using risk horizons and times to equal incidences and our findings are of interest to both patients and clinicians. For instance, from the risk horizons, if no anxiety disorder has been diagnosed within 2 months of a COVID-19 diagnosis then, from that time onwards, a patient can be reassured that their risk is no longer any greater than after another respiratory infection. If a patient had developed an ischaemic stroke within 2 months of a COVID-19 diagnosis, it is plausible that the COVID-19 diagnosis contributed (whether directly or indirectly) to its occurrence, but beyond 2 months, other causes should be actively considered. Risk trajectories are also informative for public health. An increase in the number of new cases of COVID-19 is likely to lead to an increase in the number of cases of mood and anxiety disorders but this will be short lived. By contrast, the absence of risk horizons within the first 2 years of a COVID-19 diagnosis (ie, ongoing risk trajectories) for some diagnoses (eg, psychotic disorders, epilepsy or seizures, cognitive deficit, and dementia) indicate that patients and clinicians must remain vigilant about the possibility of these delayed sequelae. These findings also suggest that service provision needs to be reinforced and sustained, because new cases are likely to occur for a considerable time after the pandemic has subsided. The time to equal incidence informs us about what happens after the risk horizon has been reached. On the one hand, the risks might become approximately equal in the two cohorts so that a so-called COVID excess remains throughout follow-up and the time to equal incidence is never reached (ie, persistent risk trajectories), which was the case for insomnia and myoneural junction or muscle disease. On the other hand, the risks might reverse, with more new diagnoses in the other respiratory infection cohort than in the COVID-19 cohort after the risk horizon, so that a time to equal incidence is eventually reached (ie, transient risk trajectories), as seen for anxiety and mood disorders.
Another important aspect of outcome trajectories is the proportion of people who received a neurological or psychiatric diagnosis who subsequently died. All-cause mortality was substantial among older adults diagnosed with neurological or psychiatric sequelae both after COVID-19 diagnosis and after another respiratory infection—notably, those with epilepsy or seizures, dementia, cognitive deficit, and psychotic disorder. The fact that similar proportions of patients with these outcomes died in both cohorts suggests that this high mortality reflects general physical ill health rather than being related to SARS-CoV-2 infection itself.
- Manja V
- AlBashir S
- Guyatt G
Because both death and the individual outcomes tend to be more common after COVID-19, the survivorship bias introduced when analysing individual outcomes brings HRs closer to 1. Individual outcomes, rather than composite outcomes with death, better reflect the burden of post-COVID-19 sequelae on health systems whereas composite outcomes are probably more informative to patients. Some outcomes have an HR of less than 1 when analysed in isolation and an HR of more than 1 when investigated as part of a composite outcome with death. Outcomes in this category are less likely to occur after COVID-19 versus after any other respiratory infection, but this might at least partly be because patients died before they could be diagnosed with these outcomes. The role of death as a competing risk likely differs between age groups because death rates vary substantially, which might contribute to apparent differences in risk profiles.
Compared with adults and older adults, children were at a particularly increased risk of epilepsy or seizures, encephalitis, and nerve, nerve root, and plexus disorder, leading to significantly higher cumulative incidence after 2 years (albeit with small absolute risks) in this age group. The persistence and severity of these outcomes cannot be determined from our study, but some will probably have deleterious consequences for children’s health and physical and educational development. Therefore, these findings inform the risks and benefits of vaccination (and other preventive measures) against COVID-19 in paediatric populations. Reassuringly, unlike adults, children were not at an increased risk of mood and anxiety disorders after SARS-CoV-2 infection (even in the first 6 months) and cognitive deficit in children had a transient risk trajectory rather than ongoing risks as seen in older groups. The difference in profiles and trajectories of risks in children might indicate that the pathogenesis of COVID-19 sequelae is different in some respects from that of adults.
- Twohig KA
- Nyberg T
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- et al.
)—for example, the HR for the composite of death or cognitive deficit was 1·38 (95% CI 1·27–1·48) whereas the HR for a diagnosis of cognitive deficit alone was 1·13 (1·02–1·26). Compared with just before the emergence of omicron, the neurological and psychiatric profile just after the emergence of omicron was broadly similar. For instance, we found no difference in the risk of cognitive deficit, epilepsy or seizures, ischaemic stroke, and psychotic disorder, and higher risks of some outcomes (eg mood disorder). All risks were largely offset by a reduced risk of death after the emergence of omicron (consistent with existing literature
- Nyberg T
- Ferguson NM
- Nash SG
- et al.
). The decreased composite risks of death and neurological or psychiatric sequelae are reassuring for patients. However, the ongoing risk of individual outcomes indicates that health services will likely continue to face a similar rate of these post-COVID-19 diagnoses even with SARS-CoV-2 variants that lead to otherwise less severe disease.
- Evans RA
- McAuley H
- Harrison EM
- et al.
,
,
Sequelae in children might in part be driven by a post-infectious immune-mediated mechanism such as acute disseminated encephalomyelitis (ADEM), as has been suggested in a prospective study of 52 children hospitalised with COVID-19.
- Ray STJ
- Abdel-Mannan O
- Sa M
- et al.
This is consistent with our observations of an increased risk of encephalitis in children only, and a higher rate of post-COVID epilepsy or seizures in children. In the whole cohort, the finding of a persisting increased risk of cognitive deficit and dementia, psychotic disorder, and epilepsy or seizures 2 years after SARS-CoV-2 infection suggests that any underlying mechanism must have ongoing activity well past the acute infection (e.g. endotheliopathy might lead to a damaged or fragile cerebral vasculature at risk of thrombotic events or recurrent leakage
). Notably, mood and anxiety disorders followed a different pattern than most other outcomes: their elevated risk subsided within 2 months, their cumulative incidence after 2 years was not increased, and children were not at greater risk at any stage after COVID-19 than after other respiratory infections. One possible explanation is that COVID-19 precipitates mood and anxiety disorders in individuals with an underlying predisposition, via a short-lived stress-related pathogenesis to which children are less susceptible.
- Taquet M
- Geddes JR
- Husain M
- Luciano S
- Harrison PJ
in which we showed that severity explains part, but not all, of the association between COVID-19 and specific neurological and psychiatric outcomes. Third, only individuals who were diagnosed early in the pandemic contributed data for the whole 2-year follow-up. This is a subgroup within the whole cohort that might not be representative of the whole cohort. Future studies should clarify risks at the 2-year time point once larger sample sizes with longer follow-up become available. Fourth, our allocation of cohorts to study variants is based on epidemiological incidence data of different variants, not individual genotyping. Hence, these cohorts are likely to contain a few cases of other variants, which we factored into the statistical power calculation. The presence of patients with different variants in each variant cohort will bring HRs closer to 1 and so differences between variants would likely be more substantial if individual genotyping were possible. Fifth, vaccination status (used in matching) is probably under-reported in TriNetX, because the prevalence of vaccination was low in both cohorts. This under-reporting might affect HRs calculated when comparing COVID-19 cohorts before and after the emergence of new variants. Selecting time windows that were close to each other mitigates this effect, but does not eliminate it. Previous vaccination is associated with reduced or unchanged risks of most neurological or psychiatric outcomes.
- Taquet M
- Dercon Q
- Harrison PJ
Therefore, the higher number of vaccinated people after (vs before) the emergence of each variant might have decreased the observed HRs. Sixth, children and adolescents were grouped together, so further studies are needed to characterise the risks in different paediatric subgroups. Seventh, although in-hospital mortality data are well captured in TriNetX, out-of-hospital mortality reporting is more variable and linkage with mortality indices is only partial, so our incidence estimates will be underestimates and should be interpreted cautiously; but HRs for composite outcomes should not be affected to the same extent. Eighth, we do not know the severity or course of each disorder after diagnosis, or whether or not these are similar after COVID-19 and after other respiratory infections.
In summary, post-COVID neurological and psychiatric outcomes followed different risk trajectories: the risk of cognitive deficit, dementia, psychotic disorder, and epilepsy or seizures remained increased at 2 years after a COVID-19 diagnosis, while the risks of other diagnoses (notably, mood and anxiety disorders) subsided early and showed no overall excess over the 2-year follow-up. Children are not at increased risk of mood or anxiety disorders (even over the first 6 months) but share adults’ risk of several other diagnoses. The comparable risks seen after the emergence of omicron indicate that the neurological and psychiatric burden of COVID-19 might continue even with variants that lead to otherwise less severe disease. These findings are relevant for policy makers involved in anticipating and addressing the health burden of the pandemic, for researchers seeking to identify the mechanisms underpinning brain sequelae of COVID-19, and for patients and clinicians wishing to know the neurological and psychiatric risks following SARS-CoV-2 infections.
MT and PJH designed the study and defined cohort inclusion and exclusion criteria, outcome criteria, and analytical approaches. MT, QD, RS, LZ, JM, and IC contributed to data processing. MT did the data analyses. MT and PJH interpreted the data. MT wrote the report with input from PJH, RS, LZ, and JM. MT and PJH accessed and verified the underlying study data. MT is the guarantor. All authors had full access to all the data in the study, and had final responsibility for the decision to submit for publication.
