Women are about three times more likely than men to develop long COVID, and many experience symptoms that linger and intensify – fatigue, brain fog, pain, shortness of breath – months after the initial infection fades.

A new study from the University of Alberta helps explain why. By comparing blood, immune-cell profiles, and gene activity in people with and without long COVID, researchers uncovered biological differences that map onto those harsher, longer lasting symptoms.

The stakes are high. As of June 2023, 3.5 million Canadians reported having had long COVID. Finding the “why” behind sex differences could finally point to “what next” for treatment.

Who is getting long COVID?

The team focused on 78 people with long COVID one year after their acute infection and compared them to 62 peers who recovered without persistent symptoms.

Many in the long COVID group never had severe disease during the acute phase.

According to principal investigator Shokrollah Elahi, the team is 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 hospitalized,” said Elahi.

That choice matters. If long COVID can follow mild infection, the triggers are unlikely to be the dramatic organ damage seen in critical illness.

Instead, the culprits may live in subtler shifts, such as immune signaling, hormonal balance, and tissue barriers that normally keep inflammation in check.

A cascade that won’t quit

One of the clearest signals in women with long COVID was evidence of gut barrier disruption, often called “gut leakiness.”

Blood levels of intestinal fatty acid binding protein (a marker of intestinal injury), lipopolysaccharide (a bacterial component), and soluble CD14 (an immune activation marker) were all elevated.

That cocktail leads to ongoing gut inflammation, with bacterial fragments crossing into the bloodstream and stoking body-wide immune responses.

“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.

If that early nudge weakens the gut barrier, the immune system can remain revved up for months – fuel for fatigue, pain, and cognitive fog.

Women develop anemia

The study also flagged dampened red blood cell production – anemia – in female participants with long COVID. Anemia can sap energy and worsen breathlessness and brain fog.

The team’s read: inflammatory signals in women with long COVID are interfering with how bone marrow makes new red cells.

That idea aligns with emerging data. An international study of more than 500 patients recently reported anemia as a core biological feature of long COVID.

Hormones out of balance

Layered on top of immune differences were clear hormone shifts. Women with long COVID showed reduced testosterone. Men showed reduced estrogen.

Both groups had lower cortisol, a hormone that helps calibrate stress and immune responses.

Lower testosterone in women correlated with higher inflammatory markers and with the very complaints patients struggle with most: brain fog, depression, pain, and fatigue.

The findings suggest the development of disrupted barriers in the gut systemic inflammation.

This inflammation blunts red blood cell production, while out-of-range sex hormones remove another brake on inflammatory pathways, especially in women.

That interplay may explain why women so often report more severe and persistent symptoms.

Treating women with long COVID

Clinically, many women in the study look like they have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that also disproportionately affects women and features chronic inflammation and debilitating fatigue.

There are differences, though. Anemia, for instance, is not a hallmark of idiopathic ME/CFS, while it does show up here. That nuance matters for tailoring care.

Because the signals are measurable – gut leak markers, inflammatory proteins, red cell indices, hormone levels – the study points to practical next steps. Elahi is planning to validate the findings in animal models of long COVID and is seeking support for a clinical trial.

The concept is personalized care: test each patient, then target what’s abnormal. That could mean treating anemia, dialing down inflammation, and, in selected cases, thoughtfully using sex-hormone therapies.

As Elahi noted, an individualized approach might include anemia treatment, anti-inflammatory drugs and even sex hormones, depending on each patient’s results.

Limitations and future steps

This was a well-characterized cohort with a clear control group, but it’s still one snapshot in time.

The researchers acknowledge that bigger, longitudinal studies are needed to see how these markers rise and fall with symptoms, and to test whether fixing them actually improves how people feel and function.

However, symptoms such as gut barrier disruption, inflammation, disordered blood production and hormone imbalance already offer a satisfying mechanistic bridge from viral infection to chronic symptoms.

Moreover, it opens doors beyond COVID. Elahi’s group plans to probe overlaps between the neurological complaints in long COVID and those seen with HIV infection – another condition where persistent immune activation and barrier dysfunction loom large.

For now, the takeaway is both sobering and encouraging. Sobering, because the drivers of long COVID in many women are layered and reinforcing. Encouraging, because they’re also testable and, potentially, fixable.

“They didn’t have these symptoms prior to COVID and most had only mild COVID-19 disease, so they were not hospitalized,” Elahi said. With the right targets in sight, the next step is turning those insights into relief.

The research is published in the journal Cell Reports Medicine.

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