Molecular and cellular level research shows a sharp sex divide for long COVID—women are more vulnerable

Scientists have identified “immune pathways” during acute coronavirus infection that are associated with the development of long COVID, and while some pathways are the same for men and women, others differ dramatically along a sharp divide between the sexes.

Long COVID has left hundreds of millions of people debilitated worldwide, some suffering a few months—others for many years. A study published in August in the journal Nature Medicine estimated that since 2020, 400 million people have had long COVID at an estimated cost of $1 trillion a year. A disproportionate number of people with long COVID are women.

A multidisciplinary team at Stanford University that explored immune pathways in the development, persistence and resolution of long COVID, say sex-based differences—and similarities—not only emerged in their research, the findings have helped shed new light on long COVID and suggest new paradigms for treatment.

Some pathways, such as alterations in monocyte activation, were shared between the sexes. Monocytes are immune cells that are part of the innate immune system—first responders—that fight infection and summon other components of the immune system to destroy invading viruses.

But the researchers also examined long COVID’s association with immune impairment—dysregulation—which is inextricably linked with multiple molecular factors, many of which are sex-dependent. Men and women, the researchers found, display unique differences in their protein expression patterns and signaling molecules, all of which underlie long COVID.

“Sex-based differences have underpinned outcomes for both acute COVID-19 and long COVID,” writes Dr. Rebecca E. Hamlin, lead author of the study published in Science Translational Medicine. “Within the first year of the pandemic, males were observed to have higher rates of critical illness and death from acute COVID-19 compared with females. Conversely, female sex has been epidemiologically associated with an increased risk of developing long COVID.

“We hypothesized that sex-specific immune dysregulation contributes to long COVID pathogenesis,” added Hamlin, noting that the team conducted a rigorous study involving 45 participants, all recruited into the analysis three months after infection.

Long COVID is a constellation of disparate health problems that emerge in the aftermath of SARS-CoV-2 infection. The U.S. Centers for Disease Control and Prevention describes long COVID as a chronic condition that can last at least three months and includes “a wide range of symptoms or conditions that may improve, worsen or be ongoing.”

Post-COVID disorders can impact the brain, heart, respiratory system or gastrointestinal tract and can range from a loss of taste and an inability to sense odors to complex cardiovascular problems, such as blood clots that increase the risks of heart attack and stroke. Countless patients have reported fatigue and “brain fog.”

All 45 participants in the Stanford study came down with COVID in 2020; 36 developed long COVID and 55% of those affected were women. Hamlin and colleagues performed a battery of tests on participants’ blood samples, examining individuals during acute infection and again at three and 12 months after infection. The aim was to study sex differences and similarities underlying COVID and the onset of long COVID. The team also studied symptom persistence and symptom resolution.

“Overall, we discovered multiple differences in the innate and adaptive immune pathways during both acute COVID-19 infection and months later in those who developed long COVID versus those who recovered,” Hamlin wrote in a post on the social media platform, LinkedIn. “Interestingly, many of those immune differences differed by sex, while some of them occurred in both sexes.”

The new findings, Hamlin underscored, suggest that future long COVID therapies should be tailored to the sex and immune response of each patient. Participants in the study produced substantial new data “affording us the opportunity to evaluate predictors of long COVID versus recovery,” Hamlin added.

That a chronic condition can emerge in the aftermath of a viral infection is not unique to SARS-CoV-2. A wide range of viruses are associated with post-infection physiological effects that emerge weeks to years after active infection has ceased. Sex differences also characterize other post-viral disorders.

Polio, for example, can result in a decades-long condition known as post-polio syndrome. Those affected experience muscle atrophy and weakness, joint pain, and mental and physiological fatigue. As is true with long COVID, studies have shown that women are more likely to develop post-polio syndrome than men.

Measles virus is related to a horrifying, though rare, post-infection condition. The devastating disorder is known as subacute sclerosing panencephalitis, which can emerge years after a measles infection and is typified by mental deterioration, muscle spasticity and seizures. The condition is invariably fatal and is more common in men than women.

A disorder called encephalitis lethargica emerged in the aftermath of the 1918 flu pandemic. The mysterious post-infection illness was characterized by brain inflammation, tremors, muscle weakness and a sleeping sickness that caused patients to fall into deep slumber that lasted weeks to months. The disorder was more common in men than women, but studies have shown that women were more likely to die during encephalitis lethargica’s acute phase.

To better understand long COVID, Hamlin and colleagues turned to multiomic analysis, studying peripheral blood samples from each participant. Multiomics allows researchers to examine a sample’s genomics, proteomics, transcriptomics and metabolomics.

In addition to the multiomic analyses, Stanford scientists also conducted single-cell RNA sequencing to determine how various cell types communicate with one another. Overall, the team discovered multiple differences in both innate and adaptive immunity between those who recovered and those who developed long COVID.

“Several sex-specific immune pathways were associated with long COVID,” Hamlin asserted. “Males who would later develop long COVID exhibited increases in transforming growth factor-β —TGF-β— signaling during acute infection, whereas females who would go on to develop long COVID had reduced TGFβ1 expression.

“Females who developed long COVID demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered,” Hamlin continued. “Many immune features of long COVID were also conserved across sexes, such as alterations in monocyte phenotype and activation state.”

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