Study reveals why women more likely to get severe long Covid

New research has uncovered biological differences that explain why women with long Covid experience more severe and persistent symptoms than men.

Long Covid is diagnosed when neurological, respiratory or gastrointestinal symptoms persist for three months or more after SARS-CoV-2 infection.

Women are about three times more likely than men to develop it, but the biology behind this gap has been unclear.

The research from the University of Alberta suggests potential treatment targets that could help the 3.5 million Canadians who reported long Covid as of June 2023, according to Statistics Canada.

Principal investigator Shokrollah Elahi is an immunology professor in the Mike Petryk School of Dentistry.

The researcher said: “We are focusing on a subset of patients with the most devastating symptoms that are very similar to chronic fatigue syndrome.

“They didn’t have these symptoms prior to Covid and most had only mild Covid-19 disease, so they were not hospitalised.”

Elahi’s team ran blood and genetic tests on 78 patients with long Covid one year after their acute diagnosis, plus 62 controls who did not develop long Covid after infection.

By analysing immune cells, blood biomarkers (measurable signals of disease) and RNA sequencing (a method to read gene activity), the researchers identified a distinct immune signature in female versus male patients.

They found evidence of “gut leakiness” in female patients — when the intestinal barrier becomes more permeable and allows substances to pass into the bloodstream — including raised levels of intestinal fatty acid-binding protein, lipopolysaccharide and soluble CD14.

These signs of gut inflammation can trigger wider inflammation once in circulation.

“This suggests that probably at the earliest stage of disease when patients get acute SARS-CoV-2 infection, there is a tendency that the females’ guts are more prone to viral infection,” Elahi said.

The team also observed lower red blood cell production — anaemia — in female patients, suggesting elevated inflammatory factors in women with long Covid may impair blood formation.

In addition, they reported dysregulated sex hormones in long Covid: reduced testosterone in affected women, decreased oestrogen in male patients, and lower cortisol in both.

Women with lower testosterone had higher inflammatory markers. Because testosterone can help dampen inflammation, reduced levels may leave women more vulnerable to ongoing inflammatory responses. Lower testosterone was also linked to brain fog, depression, pain and fatigue.

The findings suggest hormone imbalance plays an important role in long Covid, particularly in how it affects women, Elahi said.

These results mirror some features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which also disproportionately affects women.

For example, chronic inflammation is common to both, although anaemia is not typically associated with chronic fatigue.

The team’s conclusions are supported by another recent international study of more than 500 patients that also identified anaemia as a major biological driver of long Covid.

Elahi plans to validate the findings by testing potential treatments in mouse models of long Covid and is seeking funding for a clinical trial.

He proposes an individualised approach guided by test results that could include anaemia treatment, anti-inflammatory medicines and, in some cases, sex hormones.

He also aims to further explore similarities between neurological symptoms of long Covid and those seen in HIV.