New study links COVID-19 to persistent neuropsychiatric problems, highlights benefits of vaccination

A recent study published in the journal Nature Human behavior, The researchers used a large binational cohort (total n = 4,731,778) to investigate the short- and long-term association between SARS-CoV-2 infection and subsequent adverse neuropsychiatric outcomes. They used exposure-driven propensity score matching to compare outcomes in their sample with the general population and with patients with respiratory infections other than SARS-CoV-2.

study: Short- and long-term neuropsychiatric outcomes of long COVID in Korea and JapanImage credit: Kateryna Kon / Shutterstock

The study findings revealed that COVID-19 survivors were at significantly higher risk of developing cognitive impairment, insomnia, encephalitis, and at least four other neuropsychiatric sequelae. Specific conditions included Guillain-Barré syndrome (aHR, 4.63), cognitive impairment (aHR, 2.67), insomnia (aHR, 2.40), anxiety disorders (aHR, 2.23), encephalitis (aHR, 2.15), ischemic stroke (aHR, 2.00), mood disorders (aHR, 1.93), and neuro/radiculo/plexopathy (aHR, 1.47). It is encouraging to observe that vaccination reduces the neuropsychiatric impact of the infection. These results are of particular interest to clinicians and health policymakers, as they suggest that early management of COVID-19 may benefit patients' short-term and long-term mental health.

background

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is one of the worst disease events in human history, infecting approximately 700 million people and claiming more than 7 million lives in the three years since its discovery. Unfortunately for survivors, the disease has been observed to cause long-term physical and mental illnesses that persist long after primary infection with the disease.

Colloquially referred to as “long COVID,” the disease is loosely defined as persistent or new-onset multisystem disease. COVID-19 Symptoms or comorbidities persisting for more than 3 months after recovery from primary SARS-CoV-2 infection. Alarmingly, the number of long COVID-19 cases is estimated to be between 18% and 70% of COVID-19 survivors, and the recorded numbers (>65 million confirmed patients) are estimated to be only a small fraction of unrecorded global infections. Long COVID-19 is therefore one of the most oppressive medical concerns of our time.

Long COVID is a disease that has only recently been discovered and is therefore poorly understood. A growing number of studies have shown an association between Long COVID and neuropsychiatric disorders, including depression, insomnia, anxiety, and cognitive impairment, the duration of which is not uncommon for longer than 6 months. Unfortunately, previous studies aimed at comparatively assessing the risk of psychiatric disorders in COVID-19 survivors versus the general population have small sample sizes, limited follow-up periods, and, most notably, highly biased hospital-derived cohorts. The results of such studies are confusing and hinder Long COVID management and mitigation efforts.

About the Research

This binational (Korea and Japan) study aims to assess the relative risk of poor neuropsychiatric outcomes in COVID-19 survivors versus the general population, and to compare this risk between previous cohorts and survivors of other respiratory tract infections (ARIs). In this study, the primary exposure was laboratory-confirmed onset of COVID-19 (or ARI), and the primary outcome was a diagnosis of any of a group of 13 neuropsychiatric disorders.

The study datasets were divided into “discovery” and “validation.” The discovery dataset was obtained from the K-COV-N cohort, a population-based, nationally representative tally of the Korean National Health Information Database (n = 10,027,506). The validation dataset was obtained from the Japanese claims-based cohort (JMDC, n = 12,218,680). Both datasets included patient-level age (>20 years), sex, income, medical history, region of residence, and insurance claims data. All participant outcomes were recorded using World Health Organization (WHO) International Classification of Diseases (ICD-10) codes.

The study methodology used exposure-based propensity score matching to establish baseline-corrected comparisons between COVID-19 survivors and the general population or ARI, which served two purposes: to assess the robustness of the observations and to generalize the study findings across large binational sample cohorts.

Statistical analyses included calculation of Cox proportional hazards regression models ('adjusted hazard ratios'). [aHR]') was used to estimate short-term, long-term, and overall neuropsychiatric risks among the included sample subgroups (SARS-CoV-2 infection and ARI) and to induce reverse causation. Covariates were considered by including the Charlson comorbidity index, smoking status, physical activity level, alcohol consumption, and body mass index (BMI) of the included participants.

research result

The discovery and validation cohorts initially consisted of 10,027,506 and 12,218,680 participants, respectively. We excluded individuals with incomplete health records, a history of neuropsychiatric disorders, COVID-19 and ARI co-infection, and multiple confirmed COVID-19 reinfections, resulting in a final sample size of 4,731,778 participants. The mean age of study participants was 48.4 years, and 50.1% were male.

Exposure-driven propensity score matching results suggested that the ratio between COVID-19 and the general population (discovery/Korea samples) was 1:4, the ratio between COVID-19 and the general population (validation/Japan samples) was 1:2, and the ratio between COVID-19 and ARIs (discovery and validation) was 1:1.

Short-term (<30 days after recovery) risk assessment revealed that COVID-19 survivors had a significantly elevated risk of neuropsychiatric disorders (aHR = 2.35) compared to the general population, with some conditions, particularly encephalitis (aHR = 12.34), Guillain-Barré syndrome (aHR = 11.89), and insomnia (aHR = 5.36), showing surprisingly high risks. These results were consistent (albeit attenuated) with those observed in the comparison of SARS-CoV-2 infection and ARIs, where the former had an aHR of 1.36 compared to the latter.

Long-term risk assessment similarly revealed that COVID-19 survivors were significantly more likely to sustain neuropsychiatric disorders for ≥30 days compared with the general population and ARI (aHR = 1.71 and 1.60, respectively).

“The highest hazard ratio after COVID-19 diagnosis was for Guillain-Barré syndrome (aHR, 4.63; 95% CI, 1.66–12.98), followed by cognitive impairment (aHR, 2.67; 95% CI, 1.39–5.15), insomnia (aHR, 2.40; 95% CI, 2.15–2.69), anxiety disorder (aHR, 2.23; 95% CI, 2.08–2.40), encephalitis (aHR, 2.15; 95% CI, 1.18–3.94), ischemic stroke (aHR, 2.00; 95% CI, 1.64–2.44), and mood disorder (aHR, 1.93; 95% CI, 1.01–1.06). CI, 1.77–2.09) and nerve/root/plexopathy (aHR, 1.47; 95% CI, 1.36–1.59).

Time decay assessment revealed that while Koreans returned to risk levels similar to the general population 12 months after initial recovery from infection, the same was not true for the Japanese cohort. Encouragingly, patient-level risk of neuropsychiatric disorders was strongly associated with infection severity and vaccination status, with lower risk in those with mild SARS-CoV-2 infection and those receiving multiple vaccinations.

Conclusion

This study revealed an association between COVID-19 infection and an increased risk of developing neuropsychiatric sequelae in Korean and Japanese people afterward. Moreover, it is the first study to compare this risk among COVID-19 survivors, the general population, and other respiratory infections. Although the time decay results highlight the persistence of risk even 12 months after recovery from COVID-19 in Japanese people, insights into the association between infection severity/vaccination status and risk will help clinicians and health policymakers to better manage patients and this silent global pandemic.