Cho, S.-M. et al. (2024) Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after COVID-19 hospitalization: An international multicenter prospective observational study. Brain Communications, 6(2), fcae036. (doi: 10.1093/braincomms/fcae036) (PMID:38444907) (PMCID:PMC10914448)
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Abstract
Although it is known that COVID-19 can present with a range of neurological manifestations and in-hospital complications, sparse data exist if these initial neurological symptoms of COVID-19 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (PANSC) and if female versus male sex impacts the symptom resolution. In this international, multicentre, prospective observational study across 407 sites from 15 countries (January/30th/2020-April/30th/2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time. PANSC included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia, and muscle aches/joint pain, which were collected at the index hospitalization and during the follow-up assessments. The analysis considered time to resolution of individual and all neurological symptoms. Resulting times were modeled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. Model results were summarized as cumulative probability functions and age- and sex-adjusted median times to resolution. We included 6,862 hospitalized adults with COVID-19, who had follow-up assessments. The median age of participants was 57 years (39.2% females). Males and females had similar baseline characteristics except that more males (vs. females) were admitted to Intensive Care Unit (30.5% vs. 20.3%) and received mechanical ventilation (17.2% vs. 11.8%). Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median=102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. Reported prevalence in females was generally higher (vs. males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, though fatigue, altered consciousness, and myalgia remained unresolved in >10% of the cohort. Females had a longer time to resolution (5.2 vs. 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom. In multivariable analysis, males were associated with a shorter time to resolution of symptoms (Hazard Ratio=1.53; 95% Confidence Interval =1.39–1.69). Intensive Care Unit admission was associated with a longer time to the resolution of symptoms (Hazard Ratio =0.68; 95% Confidence Interval=0.60–0.77). Post-discharge stroke was uncommon (0.3% in females; 0.5% in males). Despite the methodological challenges of survey data, this international multicentre prospective cohort study demonstrates that PANSC following index hospitalization is high. Symptom prevalence was higher and took longer to resolve in females than in males. This supports that whilst males were sicker during acute illness, females were disproportionately affected by PANSC.
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| Additional Information: | This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z and 220757/Z/20/Z]; the Bill & Melinda Gates Foundation [OPP1209135]; the philanthropic support of the donors to the University of Oxford’s COVID-19 Research Response Fund (0009109); grants from the National Institute for Health Research (NIHR; award CO-CIN-01/DH/Department of Health/United Kingdom), the Medical Research Council (MRC; grant MC_PC_19059), and by the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), (award 200907), NIHR HPRU in Respiratory Infections at Imperial College London with PHE (award 200927), Liverpool Experimental Cancer Medicine Centre (grant C18616/A25153), NIHR Biomedical Research Centre at Imperial College London (award ISBRC-1215- 20013), and NIHR Clinical Research Network providing infrastructure support; the Rapid European COVID-19 Emergency Response research (RECOVER) [H2020 project 101003589] and European Clinical Research Alliance on Infectious Diseases (ECRAID) [965313]; Cambridge NIHR Biomedical Research Centre (award NIHR203312); a Research Council of Norway grant no 312780, and a philanthropic donation from Vivaldi Invest A/S owned by Jon Stephenson von Tetzchner; the Comprehensive Local Research Networks (CLRNs) of which PJMO is an NIHR Senior Investigator (NIHR201385); Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115523 COMBACTE, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013) and EFPIA (European Federation of Pharmaceutical Industries and Associations) companies, in-kind contribution; Italian Ministry of Health “Fondi Ricerca corrente–L1P6” to IRCCS (Scientific Institute for Research, Hospitalization and Healthcare) Ospedale Sacro Cuore–Don Calabria; Australian Department of Health grant (3273191); grants from Instituto de Salud Carlos III, Ministerio de Ciencia, Spain; the French COVID cohort (NCT04262921) is sponsored by Inserm (Institut national de la santé et de la recherche médicale) and is funded by the REACTing (REsearch & ACtion emergING infectious diseases) consortium and by a grant of the French Ministry of Health (PHRC n°20-0424); the South Eastern Norway Health Authority and the Research Council of Norway. Jonathon Paul Fanning is funded by a Metro-North Clinical Research Fellowship, Department of Health, Queensland Government, Australia. Sung-Min Cho is funded by National Heart, Lung, and Blood Institute 1K23HL157610. Nicole White is funded by an Advance Queensland Industry Research Fellowship (AQIRF076-2020-CV). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Scott, Dr Janet and Baillie, Dr Kenneth |
| Authors: | Cho, S.-M., Premraj, L., Battaglini, D., Fanning, J. P., Suen, J., Li Bassi, G., Fraser, J., Robba, C., Griffee, M., Solomon, T., Semple, M. G., Baillie, K., Sigfrid, L., Scott, J. T., Citarella, B. W., Merson, L., Arora, R. C., Whitman, G., Thomson, D., White, N., and ISARIC Clinical Characterisation Group, |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Brain Communications |
| Publisher: | Oxford University Press |
| ISSN: | 2632-1297 |
| ISSN (Online): | 2632-1297 |
| Published Online: | 09 February 2024 |
| Copyright Holders: | Copyright: © The Author(s) 2024 |
| First Published: | First published in Brain Communications 6(2):fcae036 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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