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
Cho S-M., Premraj L., Battaglini D., Fanning JP., Suen J., Bassi GL., Fraser J., Robba C., Griffee M., Solomon T., Semple MG., Baillie K., Sigfrid L., Scott JT., Citarella BW., Merson L., Arora RC., Whitman G., Thomson D., White N., Abel L., Abrous A., Jabal KA., Zayyad HA., Tamlihat YA.
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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%).</jats:p> <jats:p>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 &gt;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.</jats:p> <jats:p>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).</jats:p> <jats:p>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.</jats:p>