Thread by @ZdenekVrozina

Long COVID in women and men are not the same disease. They share symptoms, but diverge in biology - immune, hormonal, and genetic.
After months since the preprint -
peer-reviewed study is now out in Cell Reports Medicine.🧵

This is the complete analysis immunity, hormones, and gene expression in 78 Long COVID with ME-CFS patients.
It confirms what patients have said for years -
this condition is biological, measurable, and deeply sex-specific.

In women, the immune system never stands down.
chronic inflammation, exhausted T cells, and loss of regulatory Tregs
leaky gut - constant immune activation
high IL-6, IL-1α, TNF-α, IFN-γ
low testosterone and cortisol - hormones that normally keep inflammation in check.
It’s not overreaction. It’s immune dysregulation.
Chronic inflammation meets hormonal collapse.

They also show an expansion of CD71+ erythroid cells - immature red cells released under stress.
These cells secrete ARTN, a neurotrophic factor linked to pain & cognitive fog.
It’s measurable biology.

In men, the story is different.
Less cytokine storm, more metabolic overload. Less inflammatory chaos, more mitochondrial stress.
Low estradiol, impaired mitochondrial function.
Signs of tissue repair rather than immune fire. The body tries to fix rather than fight.
They’re running a marathon on an empty battery.

The female form looks like autoimmune neuroinflammation.
Brain fog, pain, fatigue - but rooted in measurable biology.
The male form looks like chronic metabolic exhaustion.
Same symptoms. Different mechanisms.

Transcriptomic data reveal two distinct paths.
Women - neuroinflammation, oxidative stress, TGF-β activation
Men - mitochondrial metabolism, tissue repair.
Women burn. Men rebuild.

The authors propose Long COVID is a neuro-endocrine-immune disorder -
a breakdown of communication between the brain, hormones, and immune system.
And that treatment may need to be sex-specific.
testosterone support for women,
estradiol for men,
plus targeted anti-inflammatory and gut barrier therapies.

Both groups show signs of immune exhaustion.
T cells are stuck in a hyperactivated, terminal state -
unable to return to baseline.
It’s not weakness, it’s biology -
a system trapped between inflammation and burnout.

Loss of regulatory T cells (Tregs) may be the core driver.
Without these brakes, inflammation loops endlessly -
fueling pain, unrefreshing sleep, and cognitive dysfunction.
A body that can’t turn off its own alarm.

Low cortisol across both sexes points to HPA axis dysfunction -
the stress-response system that regulates immunity and energy.
That’s why many patients feel wired but tired.
Adrenal fatigue isn’t folklore - it’s measurable in plasma.

The upregulated genes in women - RELN, MEIS2, BRINP2, FEZF2 -
are all tied to neuronal plasticity and cognition.
This is the molecular fingerprint of brain fog.
Not psychosomatic. Transcriptional.

In men, it’s a different story.
Their gene profile shows a body locked in repair mode.
PALB2, BRCA2, PARP9 - DNA damage repair
CASP5, NLRP3, CLEC4D - low-grade inflammasome activity
HIF1A, SOD2, COX7A1 - mitochondrial stress response
Instead of runaway inflammation, there’s quiet exhaustion.
Macrophages cleaning debris
mitochondria running hot
cells constantly fixing damage instead of resting.

The message is clear:
Long COVID = systemic, measurable disorder
Hormones, immunity & neurons form one network
Personalized medicine starts here.

Treatment overview
The authors don’t propose one magic bullet -
but a map of disrupted systems that could guide therapy.
Hormonal balance, immune regulation, gut integrity, and metabolic recovery.
Each reflects a measurable fault line in Long COVID biology.

Hormonal modulation is key.
Low testosterone in women, low estradiol in men,
and low cortisol in both - all linked to immune imbalance.
Restoring this axis could help reset the system’s inflammatory threshold.

The study highlights loss of Treg cells (CD39) and gut barrier damage (I-FABP, LPS-BP, sCD14).
Therapies supporting immune regulation and gut repair are needed -
to stop the constant immune activation loop at its source.

While antivirals aren’t directly tested or proposed,
the team notes lingering interferon signatures (IFI27, IFI44L, OASL) -
a hint that residual viral antigens might sustain inflammation.
Future studies may need to explore this persistence.

Shahbaz at al. Cell Reports Medicine 2025. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. cell.com/cell-reports-m…