The study findings were published in the peer reviewed journal: The Lancet Psychiatry. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(22)00260-7/fulltext
In this analysis of retrospective cohort studies, in addition to supporting previous findings of an increased risk of a range of neurological and psychiatric diagnoses in the first 6 months after COVID-19 diagnosis,3, 4, 5 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.
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.
The mortality rate in older patients also raises the issue of death as a competing risk.22 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.
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.
The risk of neurological and psychiatric diagnoses of COVID-19 was greater with the emergence of the delta variant (eg, for cognitive deficit, epilepsy or seizures, and ischaemic strokes) than just before its emergence. These risks were compounded by an increased risk of death (consistent with existing literature23)—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 literature13). 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.
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 leakage27).
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.
Our study has specific limitations in addition to those inherent in electronic health records studies. First, our COVID-19 cohorts are probably enriched for symptomatic cases because self-diagnosed or asymptomatic COVID-19 is less likely to be coded in the health record.
However, mediation by several markers of severity has been tested in our previous study,4 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.28
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.
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.
