Abstract
We investigated whether SARS-CoV-2 infection is associated with short- and long-term neuropsychiatric sequelae. We used population-based cohorts from the Korean nationwide cohort (discovery; n = 10,027,506) and the Japanese claims-based cohort (validation; n = 12,218,680) to estimate the short-term (<30 days) and long-term (≥30 days) risks of neuropsychiatric outcomes after SARS-CoV-2 infection compared with general population groups or external comparators (people with another respiratory infection). Using exposure-driven propensity score matching, we found that both the short- and long-term risks of developing neuropsychiatric sequelae were elevated in the discovery cohort compared with the general population and those with another respiratory infection. A range of conditions including Guillain-Barré syndrome, cognitive deficit, insomnia, anxiety disorder, encephalitis, ischaemic stroke and mood disorder exhibited a pronounced increase in long-term risk. Factors such as mild severity of COVID-19, increased vaccination against COVID-19 and heterologous vaccination were associated with reduced long-term risk of adverse neuropsychiatric outcomes. The time attenuation effect was the strongest during the first six months after SARS-CoV-2 infection, and this risk remained statistically significant for up to one year in Korea but beyond one year in Japan. The associations observed were replicated in the validation cohort. Our findings contribute to the growing evidence base on long COVID by considering ethnic diversity.
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Data availability
The datasets analysed during the current study are available from the NHIS, South Korea (https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do) and the JMDC, Japan (https://www.jmdc.co.jp/en/jmdc-claims-database/). This protects the confidentiality of the data and ensures that information governance is robust. Applications to access health data in South Korea should be submitted to the NHIS, South Korea. Information can be found at https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do. Applications to access health data in Japan should be submitted to the JMDC, Japan. Information can be found at https://www.jmdc.co.jp/en/jmdc-claims-database/.
Code availability
This study did not generate new or customized code or algorithms. The statistical analyses were performed using SAS (version 9.4; SAS Institute Inc.) for big-data analysis. The code used in the analysis is available from the corresponding author upon request.
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Acknowledgements
This study used the database of the KDCA and the NHIS for policy and academic research. The research number of this study is KDCA-NHIS-2022-1-632 in South Korea and PHP-00002201-04 in Japan. This research was supported by a grant from the National Research Foundation of Korea funded by the Korean government (MSIT; no. RS-2023-00248157; D.K.Y.) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (no. HI22C1976; D.K.Y.). The research was supported by a grant (no. 21153MFDS601; D.K.Y.) from the Ministry of Food and Drug Safety in 2024. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. S.C., NIHR Research Professor (NIHR303122) is funded by the NIHR for this research project. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care. S.C. is also supported by NIHR grants NIHR203684, NIHR203035, NIHR130077, NIHR128472, RP-PG-0618-20003 and by grant 101095568-HORIZONHLTH- 2022-DISEASE-07-03 from the European Research Executive Agency.
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D.K.Y. had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version before submission. Study concept and design: S.K., H.L., C.M., J.I.S. and D.K.Y. Acquisition, analysis or interpretation of data: S.K., H.L., C.M., J.I.S. and D.K.Y. Drafting of the paper: S.K., H.L., C.M., J.I.S. and D.K.Y. Critical revision of the paper for important intellectual content: S.K., H.L., J.L., S.W.L., R.K., M.S.K., A.K., L.S., G.F., L.B., M.R., G.F.L.S., E.D., S.C., J.-Y.S., A.C., H.S.S., S.L., M.S., C.M., J.I.S., D.K.Y. and P.F.-P. Statistical analysis: S.K., H.L., C.M., J.I.S. and D.K.Y. Study supervision: D.K.Y. and P.F.-P. P.F.-P and D.K.Y. are the senior authors. H.L., J.I.S. and D.K.Y. contributed equally as corresponding authors. S.K. and H.L. contributed equally as first authors. D.K.Y. is the guarantor for this study. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
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M.S. received honoraria or has been a consultant for AbbVie, Angelini, Lundbeck and Otsuka. P.F.-P. is supported by #NEXTGENERATIONEU, funded by the Ministry of University and Research, National Recovery and Resilience Plan, project MNESYS (PE0000006)—A Multiscale Integrated Approach to the Study of the Nervous System in Health and Disease (DN. 1553 11.10.2022). S.C. has declared reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, and from Healthcare Convention for educational activity on ADHD, and has received honoraria from Medice. The other authors declare no competing interests.
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Kim, S., Lee, H., Lee, J. et al. Short- and long-term neuropsychiatric outcomes in long COVID in South Korea and Japan. Nat Hum Behav (2024). https://doi.org/10.1038/s41562-024-01895-8
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DOI: https://doi.org/10.1038/s41562-024-01895-8
