Is Long COVID an Estrogen-Linked Autoimmune Disease?

A commentary published in Cell Death Discovery in 2021 proposed that Long COVID may represent an estrogen-associated autoimmune disease. The authors highlighted that women appear to be about twice as likely as men to develop Long COVID, though this difference narrows after age 60, when estrogen levels naturally decline.

The authors describe two complementary hypotheses. First, organ damage from an excessive inflammatory response could contribute to prolonged symptoms. Second, a viral infection might “unmask” an autoimmune reaction through molecular mimicry, where viral proteins resemble components of the body’s own tissues, prompting self-reactive immune responses. This mechanism could explain both the persistence of symptoms and the higher incidence in women, whose immune systems are generally more reactive.

They emphasize that these hormonal and immune differences are a double-edged sword: men are more likely to experience severe acute COVID-19, while women are more prone to post-infectious or autoimmune complications. The authors propose that identifying and characterizing autoantibodies in Long COVID patients could help clarify these mechanisms and enable the development of sex-specific diagnostic and treatment strategies.

Although their preliminary analysis of pediatric cases found no significant sex differences, they note that hormonal effects are likely smaller in children due to lower levels of sex hormone influence on immune activity.

Citation

Ortona, E., Buonsenso, D., Carfi, A., Malorni, W., & Long Covid Kids study group (2021). Long COVID: an estrogen-associated autoimmune disease?. Cell death discovery, 7(1), 77. https://doi.org/10.1038/s41420-021-00464-6