Swedish Scientists Discover Strange Blood Cell Gene Activity in Some Men with Long COVID!

Medical News: New research reveals surprising changes in red blood cell development among certain male patients still suffering from lingering COVID symptoms months after recovery
A new Finnish-Swedish study has uncovered an unusual biological clue hidden in the blood of some men struggling with long-term symptoms after a COVID-19 infection. Researchers from the University of Helsinki, Helsinki University Central Hospital, the Finnish Institute of Occupational Health, and Karolinska Institutet in Stockholm have discovered significant changes in red blood cell - related gene activity in a specific subgroup of male patients suffering from post-COVID-19 condition (PCC), more commonly known as long COVID.


Swedish Scientists Discover Strange Blood Cell Gene Activity in Some Men with Long COVID!

Long COVID, or PCC, affects roughly 10 to 20 percent of people after a SARS-CoV-2 infection - even in those with mild or asymptomatic cases. Patients may continue to experience fatigue, muscle pain, cognitive issues, and a host of other symptoms months after their initial recovery. Scientists still do not fully understand what causes these symptoms to linger. But this Medical News report highlights a key breakthrough that might bring researchers a step closer to understanding the biological basis of this puzzling condition, particularly in men.
 
Tracking Down Clues in the Blood
In this study, the researchers examined blood samples from 111 individuals who had recovered from COVID-19 during the Omicron wave in Finland. The group included 57 people who had recovered fully, 54 who continued to suffer from PCC symptoms, and 63 healthy individuals with no confirmed history of COVID-19. All participants were between the ages of 18 and 65 and had received at least two COVID-19 vaccine doses.
 
Researchers used advanced RNA sequencing technologies to analyze gene activity in blood immune cells. The idea was to see whether those with lingering symptoms had unique biological signatures compared to the recovered or healthy individuals.
 
At first glance, the study found only minor changes in blood cell gene expression between the PCC group and others. Across the full study population, there were just a few differentially expressed genes (DEGs), meaning that overall, the immune systems of people with long COVID were not significantly different from those who had recovered or never been infected.
 
But things took an interesting turn when the team looked deeper - specifically at men with PCC.
 
Unusual Red Blood Cell Activity in Male Patients
Among male PCC patients, researchers discovered a subset who had an abnormally high presence of immature red blood cells, called erythroblasts, in their blood. This was not seen in females or in males who had recovered fully.
 
These men also showed strikingly altered patterns of gene activity, especially in genes related to red blood cell development, heme metabolism (the process that allows red blood cells to carry oxygen), and bone marrow function .
 
In fact, 399 genes were found to be differently expressed in this male subgroup compared to recovered and healthy males - an unusually high number in transcriptomic studies. These gene changes may be linked to how their bodies are responding to oxygen levels, iron regulation, or inflammation.
 
Interestingly, this male subgroup also had a higher average body mass index (BMI), and several had pre-existing conditions like asthma or sleep apnea. In one extreme case, a patient had dangerously high levels of hemoglobin and red blood cells, raising concerns about potential blood disorders like polycythemia vera.
 
What This Means for Long COVID Research
While these findings do not explain all PCC cases, they point to a possible biological mechanism affecting a subset of male patients. Specifically, their red blood cells - and the genes that control them - might be responding abnormally months after infection. This suggests long COVID may affect blood and oxygen-carrying capacity in ways that scientists are only beginning to understand.
 
Previous research has shown that SARS-CoV-2 can damage red blood cell precursors by binding to receptors like ACE2 and CD147. This can lead to disturbed hemoglobin function and poor oxygen delivery. Other studies have linked COVID-19 with changes in platelet function and iron metabolism - factors that could also influence fatigue and other symptoms commonly seen in PCC.

The Finnish-Swedish study adds to growing evidence that long COVID is not a one-size-fits-all condition. Instead, it may involve several different biological processes that vary by gender, weight, immune response, and pre-existing health conditions.
 
Study Design and Analytical Details
The study used a comprehensive method that included collecting blood samples, performing RNA sequencing, and applying computational deconvolution techniques to estimate different types of cells present in the blood. The researchers performed pathway enrichment analyses to identify which biological processes were most affected by the gene expression changes.
 
In the general PCC population, only three to six genes showed statistically significant changes when compared to recovered or control groups. These included immunoglobulin-related genes such as IGHG1 and IGLC7, and NOTCH3, a gene involved in immune signaling and endothelial function.
 
In female patients, transcriptomic differences were also minimal. However, pathway analysis revealed a distinct immune signaling pathway - “Immunoregulatory Interactions Between a Lymphoid and a Non-Lymphoid Cell” - that appeared altered in women with PCC, suggesting that there may still be sex-specific immune differences at play, even if not at the gene level.
 
However, the stark contrast was in the men with high erythroblast levels, where entire sets of genes related to erythrocyte function, megakaryocyte development, and heme biosynthesis were upregulated. These changes were robust even after accounting for factors like age, BMI, and smoking.
 
What Comes Next
The researchers caution that while these findings are intriguing, they cannot yet confirm whether the erythroblast-related gene changes directly cause long COVID symptoms or are simply a consequence of underlying conditions. Still, the consistent pattern suggests this male subgroup warrants further study.

The results open the door to potential biomarkers that could be used to identify and monitor male patients at risk for prolonged post-COVID symptoms. If validated in larger studies, these blood-based signatures could lead to new diagnostic tools or treatments targeting red blood cell function and oxygen transport in long COVID patients.
 
Conclusion
The study highlights that post-COVID-19 condition is not a uniform disease but a complex and multifactorial syndrome. While most patients show only minor changes in immune cell gene expression, a specific group of male patients presents significant alterations in erythrocyte-related genes. These men show increased levels of immature red blood cells and upregulation of genes tied to heme metabolism and red blood cell production - findings that may indicate the body is trying to compensate for reduced oxygen transport or lingering inflammation. The fact that these changes persisted nearly a year after the initial infection raises concerns about long-term physiological disruptions triggered by COVID-19.
 
Importantly, these alterations were not present in females or in recovered males, suggesting a unique biological profile among affected males. Further studies with larger sample sizes and a focus on red blood cell dynamics may help unravel the full scope of long COVID and eventually lead to targeted therapeutic interventions.
 
The study findings were published in the peer reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1500997/full
 
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