Why are women hit harder by long COVID? New clues emerge

Long COVID has taken what most people assumed would be a quick illness and stretched it out far longer than anyone expected.

For many, the virus clears, but the problems don’t. People report feeling exhausted, losing focus, dealing with shortness of breath, or having stomach trouble that lingers for months after their test turns negative.

Doctors use the term “long COVID” when symptoms in the brain, lungs, or digestive system appear or persist for at least three months after the original infection.

Women are three times more likely than men to develop it, and that difference has left many people wondering why.

The biology behind long COVID

A new study aims to understand what differs in the bodies of people living with long COVID. The work focused on the biology behind the symptoms rather than simply tracking how patients felt over time.

“We are focusing on a subset of patients with the most devastating symptoms that are very similar to chronic fatigue syndrome,” said Dr. Shokrollah Elahi, an immunology professor at the University of Alberta.

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

Dr. Elahi’s team carried out blood and genetic tests on 78 patients with long COVID one year after their acute diagnosis, along with a control group of 62 people who did not develop long COVID after infection with SARS-CoV-2.

By analyzing immune cells, blood biomarkers and RNA sequencing data, they identified clear differences between female and male patients.

What’s going on in women’s guts

One of the most striking findings involved the gut. The researchers found evidence of “gut leakiness” in women with long COVID. Their blood showed elevated levels of intestinal fatty acid-binding protein, lipopolysaccharide, and the soluble protein CD14.

All of these are signs of gut inflammation that can spill over into the bloodstream and trigger inflammation throughout the body.

“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,” said Dr. Elahi.

The team also found lower red blood cell production – or anemia – in the female patients. This points to elevated inflammatory factors in females with long COVID affecting their blood production over time.

Hormones out of balance

The study uncovered changes in sex hormones that aligned with these immune and blood findings.

Women with long COVID had reduced testosterone levels, while male patients had decreased estrogen. All genders with long COVID showed lower levels of the hormone cortisol.

Women with lower testosterone levels showed higher inflammation in their blood, which makes sense because testosterone usually helps keep that in check. When those levels drop, it may leave women more at risk for the kind of ongoing inflammation seen in long COVID.

These lower hormone levels were also linked to brain fog, depression, pain, and persistent fatigue. This suggests that hormone imbalances have a real influence on how long COVID affects women.

The mix of steady inflammation and severe fatigue also appears in myalgic encephalomyelitis, or chronic fatigue syndrome, which also affects more women.

Anemia is not a feature of chronic fatigue syndrome, but chronic inflammation is a familiar part of that illness.

Anemia’s role in long COVID

The team’s results are reinforced by another recent international study of more than 500 patients. That study also reported anemia as a major biological underpinning of long COVID.

Anemia can reduce the amount of oxygen delivered to tissues, which may help explain why some long COVID patients struggle with basic daily tasks that once felt easy.

Together, these findings point to a web of immune changes, hormone shifts, and blood problems that seem to fall more heavily on women.

The distinct immune signature in female patients helps explain why their symptoms can be especially intense and long lasting.

What comes next for COVID research

Dr. Elahi plans to further verify his findings by testing potential treatments in mice with long COVID, and he is seeking funding for a clinical trial.

He proposes an individualized approach to treatment depending on each patient’s test results that might include anemia treatment, anti-inflammatory drugs and even sex hormones.

Dr. Elahi also intends to continue exploring similarities between the neurological symptoms of long COVID and those associated with HIV infection.

That kind of comparison may help doctors understand why the nervous system seems so sensitive in some people after viral infections. It may also show how targeted treatments could ease that burden for patients living with long COVID.

The full study was published in the journal Cell Reports Medicine.

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