Long COVID and Sex Differences: A Narrative Review.

Abstract

Long COVID (post-COVID-19 condition) is a heterogeneous syndrome of persistent or new symptoms after severe acute respiratory syndrome coronavirus 2 infection. While men have higher risks of severe acute COVID-19 and mortality, epidemiological studies consistently show a female predominance in Long COVID, especially among middle-aged women. Interpretation is complicated by variable case definitions (World Health Organization, Centers for Disease Control and Prevention, National Institute for Health and Care Excellence) and variant-era differences; however, sex disparities persist across both pre-Omicron and Omicron periods. We review evidence on sex differences in epidemiology, symptom clusters, and longitudinal trajectories, incorporating recent RECOVER findings and emerging data from Japanese cohorts. Potential mechanisms include sexually dimorphic antiviral immunity, hormonal and X-chromosome-linked immunoregulation, autoimmunity, autonomic dysfunction, and gender-related social exposures and health-care access. Recognizing sex- and gender-related determinants can improve differential diagnosis, risk stratification, and individualized management, and should be embedded as core variables in future mechanistic studies and clinical trials.