Summary: New research reveals that women with long COVID show distinct biological alterations, including intestinal inflammation, anemia, and abnormal hormone levels, which may explain their heightened and persistent symptoms. These findings emerged from immunological, biomarker and genetic analyzes in people one year after infection.
Hormonal imbalances, especially reduced testosterone in women, were strongly linked to ongoing inflammation and symptoms such as fatigue and brain fog. The study highlights new biological targets that could help guide individualized treatments for long COVID.
Key facts
Intestinal inflammation: The women showed strong signs of intestinal permeability, leading to widespread inflammation. Hormonal disruption: Reduced testosterone in women was correlated with worse symptoms and higher inflammatory markers. Link to anemia: Female long COVID patients showed reduced red blood cell production, supporting emerging evidence of anemia as a central mechanism.
Source: University of Alberta
Research published today in Cell Reports Medicine reveals key biological differences that may explain why women with long COVID, especially those who develop chronic fatigue syndrome, tend to experience more severe and persistent symptoms than men.
Post-COVID-19, or long COVID, is diagnosed when neurological, respiratory, or gastrointestinal symptoms develop or continue three months or more after an acute SARS-CoV-2 infection.
Women are three times more likely to develop long COVID than men, but the underlying biological mechanisms driving this disparity are so far unknown.
The new research suggests potential targets for treatment that could provide relief to the 3.5 million Canadians who reported having long COVID in June 2023, according to Statistics Canada.
“We are focusing on a subset of patients with the most devastating symptoms that are very similar to chronic fatigue syndrome,” explains lead researcher Shokrollah Elahi, professor of immunology at the Mike Petryk School of Dentistry. “They didn’t have these symptoms before COVID and most only had mild COVID-19 illness, so they weren’t hospitalized.”
Elahi’s team conducted blood and genetic testing on 78 long COVID patients a year after their acute diagnosis, as well as a control group of 62 people who did not develop long COVID after SARS-CoV-2 infection.
By analyzing immune cells, blood biomarkers, and RNA sequencing, they identified a distinct immune signature in female and male patients.
They found evidence of “intestinal permeability” in the patients, including elevated blood levels of the intestinal fatty acid binding protein lipopolysaccharide and the soluble protein CD14, all signs of intestinal inflammation that can then trigger further systemic inflammation once they reach the circulatory system.
“This suggests that probably at the earliest stage of the disease, when patients get an acute SARS-CoV-2 infection, there is a tendency for women’s intestines to be more prone to viral infection,” says Elahi.
The team also found lower red blood cell production, or anemia, in the female patients. This suggests that elevated levels of inflammatory factors in women with long COVID negatively affect their blood production, Elahi says.
Additionally, researchers discovered dysregulated sex hormones in long COVID patients, finding reduced levels of testosterone in affected women and decreased estrogen in male patients, as well as lower levels of the hormone cortisol in both.
The researchers reported that women with lower levels of testosterone had higher levels of inflammation in their blood. Researchers postulate that testosterone normally helps control inflammation, so reduced levels may make women more vulnerable to ongoing inflammatory responses. Lower testosterone levels were also linked to symptoms such as brain fog, depression, pain, and fatigue.
The findings suggest that hormonal imbalances could play a big role in long COVID, particularly in how it affects women, Elahi says.
These results are similar, but not identical, to those found in idiopathic chronic fatigue syndrome (of unknown cause), now known as myalgic encephalomyelitis/chronic fatigue syndrome or ME/CFS, which also disproportionately affects women. For example, anemia is not associated with chronic fatigue, but chronic inflammation is a feature.
Elahi’s team’s findings are reinforced by another recent international study of more than 500 patients, which also reported that anemia is an important biological underpinning of long COVID.
Elahi plans to further verify his findings by testing potential treatments in mice that have long COVID, and is seeking funding for a clinical trial.
It proposes an individualized treatment approach depending on each patient’s test results that could include treatment for anemia, anti-inflammatory medications, and even sex hormones.
He also intends to continue exploring similarities between the neurological symptoms of long COVID and those associated with HIV infection.
Funding: The research was funded by the Canadian Institutes of Health Research and the Li Ka Shing Institute of Virology. Elahi’s co-authors include postdoctoral fellow Shima Shahbaz, winner of the CIHR Research Excellence, Diversity and Independence (REDI) Award for Early Career Transition; Mohamed Osman, assistant professor of medicine; Jan Willem Cohen Tervaert, professor of medicine; Rhonda Rosychuk, professor of pediatrics; Andrew Mason, professor of medicine; and Hussain Syed, medical graduate researcher. Some of the work was carried out at the U of A’s Flow Cytometry Facility and Advanced Cell Exploration Core.
Elahi, Osman and Mason are members of the Li Ka Shing Institute of Virology, the Women’s and Children’s Health Research Institute (WCHRI), and the Cancer Research Institute of Northern Alberta (CRINA). Rosychuk is a member of WCHRI. Elahi is also a member of the Glycomics Institute of Alberta and the Alberta Transplant Institute.
Key questions answered:
A: The study found that women show stronger inflammation, intestinal permeability, anemia and hormonal alterations, all related to more persistent symptoms.
A: Elevated inflammatory biomarkers, altered red blood cell production, and altered sex hormones were key differences between affected women and men.
A: The results point towards personalized therapies targeting inflammation, anemia and hormonal imbalance.
About this long COVID research news
Author: Michael Brown
Source: University of Alberta
Contact: Michael Brown – University of Alberta
Image: Image is credited to Neuroscience News.
Original research: Open access.
“Integrated immune, hormonal and transcriptomic profiles reveal sex-specific dysregulation in long COVID patients with ME/CFS” by Shokrollah Elahi, et al. Cell Report Medicine
Abstract
Integrated immunological, hormonal and transcriptomic profiles reveal sex-specific dysregulation in long COVID patients with ME/CFS
Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Our study reveals that female LC (FCL) patients with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and exhausted regulatory T cells, suggesting persistent immune activation. Elevated CD71+ erythroid cells and impaired erythropoiesis contribute to fatigue and tissue damage in the CFL.
The cytokine profile indicates a stronger proinflammatory response in LCF compared to men (LCM), along with markers of intestinal barrier dysfunction.
Hormonal analysis shows a reduction in testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, which could explain cognitive symptoms.
We also identified biomarkers that distinguish LCF from MCL and correlate with sex-specific clinical symptoms. In general, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with women exhibiting more severe inflammation.
These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.
