🔁 If you know patients with Long COVID or ME/CFS — or clinicians treating them — please share this.
Early endocrine evaluation could prevent years of avoidable deterioration in a subset of patients.
Screening is simple.
Permanent damage is not.
Let’s stop missing what is testable.
⏳ When will early endocrine intervention become standard of care?
Because delayed recognition may turn reversible dysfunction into permanent damage.
And that is avoidable.
The literature is there.
The precedent is there.
The replication is there.
Yet it remains under-recognized.
Final thought
We are not proposing something new.
We are pointing out something that already happened once — and is happening again.
How many patients are told “your labs are normal” while sitting at the lower edge of cortisol reserve?
7️⃣The bigger picture
This is not about one virus
It is a recurring pattern:
Viral infection → inflammatory/autoimmune pituitary involvement → secondary hypocortisolism → chronic symptom persistence
6️⃣ The uncomfortable question
If we already knew this from SARS-1…
And similar findings are now documented in SARS-CoV-2…
Why is early endocrine screening not standard in Long COVID?
Morning cortisol alone is not enough.
Dynamic testing (ACTH stimulation, ITT) is often required.
If secondary adrenal insufficiency is not recognized early:
• Chronic hypocortisolism persists
• Inflammation worsens
• Autonomic instability increases
• Recovery becomes harder
Early detection could prevent long-term endocrine damage.
5️⃣ Why does this matter?
HPA-axis damage is not trivial.
The adrenal glands and pituitary have:
⚠️ Very low regenerative capacity
⚠️ Slow cellular turnover
⚠️ Limited repair once chronic fibrosis sets in
In other words:
SARS-1 mechanism documented (2005)
↓
Mechanistic extrapolation to SARS-CoV-2 (our review, July 2024)
↓
Clinical confirmation in SARS-CoV-2 (August 2024)
History repeating itself.
4️⃣ And then what happened?
One month after our review was published…
A new SARS-CoV-2 paper reported pituitary involvement and secondary adrenal insufficiency in COVID-19.
ec.bioscientifica.com/view/journal...
– inflammatory hypophysitis
– or autoimmune processes targeting hypothalamus/pituitary
Again, review here:
www.frontiersin.org/journals/imm...
Because this pattern had already happened.
3️⃣ What did we write in 2024?
In our review, we argued that:
• SARS-CoV-2 shares high genetic similarity with SARS-CoV
• Therefore, similar HPA-axis vulnerability is biologically plausible
• Hypocortisolism in Long COVID may reflect:
– direct viral injury
Post-mortem data (Wei et al.) also showed reduced corticotroph staining.
This was not psychosomatic.
It was endocrine.
Importantly:
• It was often reversible
• Early recognition mattered
• It strongly suggested inflammatory pituitary damage
Original study:
onlinelibrary.wiley.com/doi/10.1111/...
2️⃣What happened with the first SARS (2003)?
After the original SARS-CoV outbreak, Leow et al. (2005) showed that ~40% of SARS survivors developed secondary adrenal insufficiency, likely due to pituitary involvement.
👉 Hypocortisolism in ME/CFS and Long COVID may result from direct infection or immune-mediated damage of the HPA axis (hypothalamus–pituitary–adrenal).
Our review:
www.frontiersin.org/journals/imm...
Read this thread — and consider discussing testing with your doctor. 👇
1️⃣ HPA axis damage in Long COVID and ME/CFS is not new. We’ve seen this before.
In July 2024, in our review, we discussed something many still overlook:
🔴🚩🧵 What if part of severe Long COVID and ME/CFS is not “mysterious” — but untreated, potentially reversible HPA-axis damage?
We already saw this after SARS-1.
It happened again with SARS-CoV-2.
And almost no one is screening for it.
Some of the worst symptoms may be preventable.
🔴🧬 1) New study on EBV confirms an immunogenetic model we had already proposed
A new immunology study provides solid evidence that the persistence of Epstein–Barr virus (EBV) is modulated by how HLA class II molecules present viral antigens to CD4⁺ T cells. 🧵
👉🏼 www.nature.com/articles/s41...
17) 📣 If you find this information relevant, sharing it or following the page helps it reach those who may need it.
#EBV #HLA #Autoimmunity #MECFS #LongCOVID
16) Because it allows us to:
📌 identify susceptibility to viral persistence
📌 anticipate the risk of chronic immune dysfunction
📌 stratify patients for early follow-up
📌 move toward preventive immunogenetic medicine
15) -patients with persistent viral infections
-ME/CFS
-long COVID
-post-infectious inflammatory syndromes
-individuals at risk of autoimmunity after infections
14) 📣 Clinical implication: HLA-II typing as a preventive tool
Taken together, these studies point in a clear direction:
🧬 HLA-II haplotype typing should be incorporated into:
13) share features of emerging autoimmune diseases, in which:
-there is an infectious trigger (often EBV, SARS-CoV-2, or intracellular pathogens with immune evasion mechanisms)
-antigen persistence occurs
-ancestral host HLA-II shapes the immune response
-loss of tolerance and autoreactivity develop
12) -ME/CFS
-long COVID
-post-viral syndromes
-autoimmune diseases
🧬 A shared framework: emerging autoimmune diseases driven by antigen persistence
The convergence of evidence supports that:
➡️ ME/CFS
➡️ long COVID
➡️ post-vaccinal syndromes in predisposed individuals
➡️ post-infectious syndromes
11) 🎯 This new work on EBV confirms—through a different approach—exactly the same model:
Viral persistence + specific HLA-II antigen presentation → chronic immune activation → loss of tolerance → autoimmune phenomena
This is the same pathogenic sequence we had previously proposed for:
10) 👉 We proposed that these same haplotypes also shape the immune response to EBV, favoring viral persistence and prolonged inflammation.
👉🏼 www.frontiersin.org/journals/imm...
🔗 The new study provides important validation
9) -increased risk of persistent immune responses and autoreactivity
-implicated in MS, lupus, RA, T1D, and most autoimmune diseases, including ME/CFS, long COVID, and post-vaccinal syndromes
8) 👉🏼 link.springer.com/article/10.1...
📌 Ancestral HLA-II haplotypes and autoimmune diseases
(Frontiers in Immunology, 2025)
Here we linked the genetic component to other autoimmune diseases:
-DR2-DQ6, DR3-DQ2, DR4-DQ8
-haplotypes with broad and potent antigen presentation
7) We showed that:
-ME/CFS and long COVID share an EBV reactivation/persistence axis
-leading to a state of chronic immune dysfunction
-with sustained inflammation, impaired antiviral surveillance, and multisystem symptoms, particularly in patients with ancestral HLA-II haplotypes.
6) We proposed that the inability to control EBV-infected cells is a key driver of pathophysiology in patients with HLA-II genetic susceptibility.
👉🏼 www.frontiersin.org/journals/imm...
📌 EBV-induced acquired immunodeficiency in ME/CFS and long COVID
(Journal of Translational Medicine, 2023)