Hypothesis Hypocortisolemic ASIA: A vaccine-and chronic infection-induced syndrome behind the origin of long COVID and ME, 2024, Ruiz-Pablos et al

Hypocortisolemic ASIA: A vaccine-and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis (Provisionally accepted)

Manuel Ruiz-Pablos 1, Aintzane Zabaleta 2, Bruno Paiva 2

• 1 Complutense University of Madrid, Madrid, Madrid, Spain
• 2 Center of Applied Medical Research, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Navarre, Spain

Abstract
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances.

A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH.

As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology. It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene.

In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress. Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Link (Frontiers in Immunology)

 

Similarities in symptoms doesn't mean that the same mechanism is responsible. There may be (likely is) some mechanisms involved in these disorders, but there could be many not involved and many extras in one or another. It seems likely that all the suggested treatments have been tried already, without success.

 

Full paper now available:
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full

 

New article: the connection between Long COVID, Myalgic Encephalomyelitis, and post-vaccinal syndromes lies in the development of an Autoimmune Hypocortisolemic Syndrome

I am excited to share with you our latest paper entitled "Hypocortisolemic ASIA: A vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis". In this paper, we explain the links between Long COVID, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (ME/CFS) and COVID-19 post-vaccine syndromes. Stay reading to the end and you will also find our treatment proposal that could improve symptoms.

➡️ Explanation on Twitter/X: https://twitter.com/user/status/1810684456866329037


➡️Link of our review article: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full

Abstract: We present a model for the development of these diseases that involves a complex interplay between immune hyperactivation, autoimmune hypophysitis or pituitary hypofunction, and immune exhaustion. We believe that the starting point is a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1). This would follow from an uncontrolled immune response with hyperactivation of CD8 T cells and elevated antibody production, some of which could be directed against self-antigens, triggering autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH.

What's the big deal?
1️⃣ Relationship to ASIA Syndrome: We propose that Long COVID, ME/CFS and post-vaccine COVID-19 syndrome could be included in adjuvant-induced autoimmune/inflammatory syndrome (ASIA) due to their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene.

2️⃣ Developmental Model: We suggest that these diseases begin with a deficient immune response and progress to uncontrolled immune hyperactivation, followed by immune exhaustion, exacerbating symptoms and pathology.

3️⃣Hypocortisolemia: We highlight the decrease in ACTH production and its impact on immune function and clinical symptoms, establishing a direct link with pituitary dysfunction.

4️⃣ Treatment Proposal: We propose a treatment approach including antivirals, corticosteroids/ginseng, antioxidants and metabolic precursors to improve symptoms by modulating immune response, pituitary function, inflammation and oxidative stress.

Implications and Conclusions:

These disorders could have an autoimmune origin against the adenohypophysis.
Treatment with antivirals and corticosteroid replacement therapy in patients with permanent pituitary damage could improve symptoms by addressing immune and hormonal dysfunction.


The key is pituitary damage: how does this relate to the development of ME/CFS, Long COVID, and other post-viral and post-vaccine syndromes?

Certain viruses (and other pathogens) and vaccines can affect the pituitary gland, interfering with cortisol production and triggering a cascade of complex symptoms. In patients with weak HLA-DRB1 alleles, such as DR15, immune hyperactivation can trigger an autoimmune response against ACTH, crucial for cortisol production. This is exactly analogous to how other autoimmune diseases such as multiple sclerosis or lupus develop, where the immune system attacks other antigens in the body, but in the syndromes we are discussing, the autoimmunity is specifically directed against pituitary ACTH.

This link explains why patients with chronic infections often experience persistent hypocortisolemia, as the pathogen continues to produce ACTH-mimicking antigens, maintaining the active autoimmune response or generates direct pituitary damage. In contrast, patients without chronic infections and with the same weak alleles treated with immune checkpoint inhibitors (ICIs) may develop temporary hypophysitis and similar cortisol deficits, but discontinuation of treatment usually allows recovery.

This also explains why patients experience chronic fatigue, dysautonomia, orthostatic intolerance, exercise intolerance, intolerance to stressful events and mild hypoglycemia due to low cortisol. Cortisol is crucial in providing the body with needed energy and regulating the stress response. When cortisol levels are low, as they are in these syndromes, the body cannot respond effectively to physical and emotional demands.

Cortisol plays a crucial role in maintaining stable blood sugar levels by promoting gluconeogenesis (glucose production) and stimulating the release of stored glucose in the form of glycogen in the liver. When there is insufficient cortisol, the body faces difficulties in increasing glucose levels in demand situations, such as during physical exercise or in response to stress, which can lead to episodes of mild hypoglycemia. In times of fright or anger, adrenaline release may temporarily improve symptoms by temporarily increasing glucose availability, briefly compensating for cortisol deficiency. However, this response does not adequately replace the long-term regulatory functions of cortisol, so symptoms may return once adrenaline subsides.

️‍♂️ In the case of physical exercise, which naturally increases cortisol levels to mobilize energy and respond to physical exertion, the lack of this hormone limits the body's ability to maintain sustained physical activity. Patients may experience rapid muscle fatigue, feelings of weakness and slower recovery after exercise.

As for stressful events (exams, travel, surgical operations, etc) , cortisol also plays a crucial role in the body's response to emotional or physical stress. When cortisol levels are insufficient, the body has difficulty handling stressful situations effectively. This can manifest itself in an exacerbation of existing symptoms, such as intense fatigue, dizziness, difficulty concentrating and a generalized feeling of malaise.

➡️ For years, many of these patients have been misunderstood and mislabeled as having psychosomatic illness. This is because their symptoms tend to worsen during periods of stress, which has led to the suggestion that the origin of their problems lies in psychological factors. However, the reality is that these patients are not experiencing symptoms due to an underlying psychological disorder, but as a direct result of insufficient cortisol. The lack of this vital hormone prevents the body from adapting and responding appropriately to stress, which perpetuates and aggravates their physical symptoms.

The Development of Autoimmunity to ACTH: A Process Similar to Other Autoimmune Diseases such as Multiple Sclerosis
This same mechanism occurs in other autoimmune diseases. Some HLA-II alleles, such as the DR15 variant, are associated with an impaired ability to recognize cells infected with certain pathogens, such as Epstein-Barr virus (EBV). In multiple sclerosis this poor recognition ability specifically affects CD4 T cells, which are crucial for coordinating the immune response. When CD4 T cells cannot correctly recognize infected cells, this leads to hyperactivation of CD8 T cells and an increase in antibodies against the pathogen to compensate for the deficient CD4 T cell response. Without the coordinated help of CD4 T cells, CD8 T cells cannot eliminate all EBV-infected cells, thus never effectively eliminating or controlling the infection and resulting in chronic infection. This results in an increase of infected cells, an exhaustion of CD8 T cells and an increased risk of developing autoimmune diseases, since CD4 T cells, by misrecognizing these viral antigens presented on the HLA-II antigen-presenting cells, can confuse them with the body's own proteins, generating an autoimmune disease. In multiple sclerosis, autoimmunity develops when the EBNA-1 antigen of the Epstein-Barr virus is mistaken for myelin, due to a similar amino acid sequence and molecular mimicry in patients with DR15 alleles. The same could occur in patients with Long COVID, myalgic encephalomyelitis and post-vaccinal syndromes, where autoimmunity against ACTH develops.


Why Vaccines Can Develop Pathologies Similar to Persistent COVID and Post-Infectious ME/CFS?

Common Mechanism: Uncontrolled Immune Activation.
Both persistent COVID and post-infectious ME/CFS and post-vaccine syndrome share a common basis: an overactive immune response. In our study, we propose the presence of:

1️⃣ Persistence of Viral Antigens or Adjuvants:
▪️Chronic viral infection: after a viral infection, such as SARS-CoV-2 or Epstein-Barr virus (EBV), viral antigens may remain in the body, triggering a continuous immune response.

▪️ Vaccination: Vaccines contain adjuvants designed to stimulate the immune system. In genetically predisposed individuals (HLA-DRB1), this stimulation may be excessive, leading to uncontrolled immune activation similar to a viral infection. In addition, the introduced viral antigens could have molecular mimicry with ACTH, exacerbating the immune response and potentially contributing to the development of autoimmunity against ACTH.

2️⃣ Autoimmunity Against the Adenohypophysis:
* Both conditions can lead to autoimmune inflammation of the adenohypophysis (autoimmune hypophysitis), resulting in hormonal dysfunction, especially ACTH production.

3️⃣ Hypercortisolemia and HPA Axis Hypofunction:
* Chronic inflammation and proinflammatory cytokine production can alter the hypothalamic-pituitary-adrenal (HPA) axis, leading to low cortisol levels, which exacerbate fatigue and other symptoms.

Cycle of Hyperactivation and Immune Depletion:
▪️ Initial Hyperactivation: Initial immune response is excessive, with high cytokine production and CD8 T-cell activation.

▪️ Immune exhaustion: Over time, this hyperactivation leads to T-cell exhaustion, decreasing the body's ability to control infection and exacerbating the pathology.

▪️ Hypocortisolism: Insufficient cortisol maintains the state of immune hyperactivation, perpetuating inflammation and hindering resolution of the immune cycle.

Evidence and Clinical Similarities:

▪️ Shared Symptoms: chronic fatigue, muscle and joint pain, sleep disturbances, cognitive problems, and post-exertional malaise.
▪️ Common Genetic: Polymorphisms in the HLA-DRB1 gene predispose to an exaggerated immune response to both viral infections and vaccine components.

Conclusion: Our review suggests that both Long COVID and post-infectious ME/CFS and post-vaccination syndromes could be considered as part of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). These findings underline the need for a personalized therapeutic approach that takes into account the genetic predisposition and immune status of the patient.

How Can Some Vaccines Trigger Persistent Health Problems?
1️⃣ Mechanism of Action:
▪️ Vaccines contain adjuvants and antigens designed to stimulate robust immune responses.
▪️ In some cases, this stimulation can lead to a dysregulated autoimmune response, similar to that seen in diseases such as systemic lupus erythematosus.

2️⃣ Vaccines Involved:
▪️ COVID-19: Cases of prolonged symptoms after infection or vaccination, known as Long COVID or post-COVID syndrome, have been reported.
▪️ Hepatitis B and C, HPV: Some individuals develop ME/CFS after vaccination, related to autoimmunity and immune alterations.

3️⃣ Risk Factors:
▪️ Genetic predisposition such as polymorphisms in the HLA-DRB1 gene may increase susceptibility to abnormal immune responses.
▪️ Viral persistence or chronic antigen exposure may trigger a continuous and pathologic immune response.

Did you know that vaccines designed with adenoviruses may have a slightly increased risk of triggering prolonged immune responses compared to messenger RNA vaccines?

Adenoviruses used as vectors may persist longer in the body, exposing the immune system to viral components for extended periods.

Adenoviruses are linear double-stranded DNA viruses and remain in an episomal condition in the nucleus. The mechanism of adenovirus vector persistence has not yet been elucidated. But they can persist for a long time in the organism. It is thought that it could be by their integration into the genome or by episomal gene duplication facilitated by the transcription machinery of the host cells. That is, it could happen that it transmits episomes to its cells as occurs in Epstein-Barr virus without lytic phase. During mitosis, EBV episomes are bound to chromosomes in metaphase through EBNA-1, allowing efficient segregation of episomes into daughter cells.

This theoretical phenomenon could predispose certain genetically susceptible individuals to develop chronic autoimmune or inflammatory disorders, as discussed in the context of ASIA syndrome. In contrast, messenger RNA vaccines, by rapidly degrading after inducing the desired immune response, limit this prolonged exposure.

⚠️ Regardless of the type of vaccine against COVID-19 or other pathologies, whether messenger RNA or adenoviral vector, there is a theoretical possible risk of developing autoimmune disease only in individuals with certain genetic alleles, such as HLA-DRB1. The key lies in prolonged exposure to viral antigens, which could trigger persistent autoimmune responses.

mRNA vaccines are characterized by rapidly degrading after inducing the desired immune response, thus limiting prolonged exposure to viral components. In contrast, adenoviral vector-based vaccines can persist in the body longer, potentially increasing the risk of a longer-lasting autoimmune reaction in susceptible individuals.

It is crucial to remember that these risks are rare when compared to the total number of vaccinated individuals and that all vaccines, including adenovirus and messenger RNA vaccines, are critical to combat pandemic diseases such as COVID-19 at the species level. However, understanding these differences may help improve future vaccine design and surveillance for potential adverse effects in these susceptible individuals.

Recall that vaccines save millions of lives and prevent serious consequences of infections in the majority of the population. However, it is crucial to recognize that they may also present risks in some susceptible individuals.

HLA-DRB1 genetic alleles play a crucial role in predisposition to diseases such as Long COVID, myalgic encephalomyelitis (ME/CFS) and ASIA syndrome, as well as in post-vaccine syndromes.

These HLA-DRB1 alleles are part of the HLA (human leukocyte antigen) system, which regulates how the immune system recognizes and responds to foreign antigens, such as viruses and vaccine components. In individuals with certain HLA-DRB1 alleles, the immune system may trigger excessive or inappropriate responses to these antigens, leading to autoimmune conditions and inflammatory syndromes.

This explains why some patients, after significant viral infection or vaccination, may develop persistent autoimmune reactions. In the case of Long COVID and ME/CFS, persistence of viral antigens could trigger an autoimmune response against self tissues, including the pituitary gland.

✨ In a key study, patients who developed hypophysitis after infection with the first SARS-CoV recovered their health months after treatment with replacement corticosteroids. This finding underscores the importance of detecting hypophysitis early to prevent permanent damage.➡️ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188349/

Hypophysitis can cause a decrease in ACTH production, crucial for adrenal function and immune response. Controlling ACTH levels is critical if symptoms such as chronic fatigue, orthostatic hypotension and sleep disturbances are present after a viral infection.

Early administration of replacement corticosteroids can stop ACTH secretion and prevent autoimmunity against this hormone, thus protecting the pituitary from further damage. Over time, as hypophysitis and viral infection subside, the dose of replacement corticosteroids can be gradually reduced until normal pituitary function is restored.


Challenges in HPA Axis Evaluation in Patients with Long COVID, ME/CFS and Post-Vaccine Syndromes.
Studies are often limited to single morning cortisol measurements, ignoring diurnal variability and cortisol response to physical/mental stress, which may underestimate problems in the HPA axis. In addition, CRH or ACTH stimulation tests, crucial for assessing pituitary and adrenal function, are not frequently performed.

It is crucial to detect HPA axis dysfunctions as early as possible to prevent adrenal atrophy due to low ACTH levels. Newly diagnosed patients may recover HPA axis function if autoimmune or direct damage by infection to the pituitary is detected early. Conversely, as time passes, the risk of pituitary damage from autoimmunity against ACTH increases, leading to further adrenal atrophy and the need for hydrocortisone replacement therapy. Early detection and treatment of these dysfunctions is crucial to improve the clinical management and quality of life of these patients.

Proposed Action Protocol for Chronic Cases or Over 6 Months with Long COVID, ME/CFS, or Post-Vaccine Syndromes with Pituitary Damage:

➡️ Initial Evaluation:
Laboratory and Imaging Tests: Pituitary MRI, Serum cortisol, saliva cortisol, 24h urine cortisol, plasma ACTH, DHEA-S and stimulation tests such as Synacthen test (synthetic ACTH stimulation test) to assess the status of the cortisol-producing adrenal glands. The diagnostic value of Synacthen lies in the assumption that chronic ACTH deficiency leads to adrenal atrophy and a consequent diminished response to stimulation with synthetic ACTH. A diagnosis of secondary adrenal insufficiency can also be confirmed with CRH stimulation testing.

➡️ Initial Treatment:
If presenting pituitary with decreased ACTH, initiate treatment with oral hydrocortisone to decrease the damage caused by autoimmunity to pituitary ACTH.

➡️ Follow-up:
-Perform cortisol and ACTH tests every 3 months during the first year .
-Repeat Synacthen stimulation tests to assess HPA axis recovery.

➡️ Evaluation of HPA Axis Recovery:
️ If post-stimulation cortisol is greater than 550 nmol/l:
-Consider gradually reducing the dose of hydrocortisone under medical supervision.
-Periodic post-suspension assessments to ensure that the HPA axis remains functional and that ACTH and cortisol levels remain at normal levels.

️ If post-stimulation cortisol is less than 550 nmol/l or there are symptoms when reducing hydrocortisone:
1️⃣ Hydrocortisone Maintenance:
Maintain hydrocortisone therapy at appropriate doses to control symptoms and avoid adrenal insufficiency.
2️⃣ Regular Monitoring:
-Periodic cortisol and ACTH assessments.

-Adjust hydrocortisone dose based on test results and clinical presentation.

-Consider other hormonal treatments if deficiencies in other pituitary hormones are identified (e.g. thyroid consequences, DHEA).

 

Proposed Action Protocol for New Cases or Less Than 6 Months Old with Long COVID, ME/CFS or Post-Vaccine Syndromes with Pituitary Damage:

➡️ Initial Evaluation:
Laboratory and Imaging Tests: Pituitary MRI, Serum cortisol, saliva cortisol, 24h urine cortisol, plasma ACTH, DHEA-S and stimulation tests such as Synacthen test. ACTH testing may not be accurate in these patients when they present with secondary adrenal insufficiency for a shorter period because their adrenal glands have not yet shrunk and may still respond to ACTH. In such situations, CRH stimulation tests may be more appropriate, as they assess the ability of the pituitary to secrete ACTH. A low or absent ACTH response on CRH testing would indicate a problem at the pituitary level.

➡️ Initial Treatment:
If presenting pituitary with decreased ACTH, initiate treatment with oral hydrocortisone to decrease the damage caused by autoimmunity to pituitary ACTH.

➡️ Follow-Up:
-Perform cortisol and ACTH tests every 3 months during the first year .
-Repeat stimulation tests to assess HPA axis recovery.

➡️ Evaluation of HPA Axis Recovery:
️ If post-stimulation ACTH is in normal ranges:

-Consider gradually reducing the dose of hydrocortisone under medical supervision.
-Periodic post-suspension assessments to ensure that the HPA axis remains functional and that ACTH and cortisol levels remain at normal levels.

️ If post-stimulation cortisol is below normal levels or there are symptoms when reducing hydrocortisone:

1️⃣ Hydrocortisone Maintenance:
Maintain hydrocortisone therapy at appropriate doses to control symptoms and avoid adrenal insufficiency.

2️⃣ Regular Monitoring:
-Periodic cortisol and ACTH assessments.
-Adjust hydrocortisone dose based on test results and clinical presentation.
-Consider other hormonal treatments if deficiencies in other pituitary hormones are identified (e.g. thyroid consequences, DHEA



Treatment Protocols Patients with Persistent COVID, Long-COVID, ME/CFS, or Post-Vaccine Syndromes with Pituitary Damage:

1️⃣ Corticosteroids/Korean Red Ginseng:
▪️ How Do They Help? May reduce inflammation and regulate immune response. Reduces NF-kB pathway by decreasing oxidative stress and antioxidant intake. Corticosteroids in replacement doses are useful in cases of permanent pituitary damage, while ginseng may be beneficial in the long term by decreasing the production of proinflammatory cytokines and improving immune and adrenal function in cases with HPA axis disruption.

▪️ Important: In cases where mildly low cortisol levels are present, ginseng treatment alone could be started to assess whether cortisol levels increase naturally. If no improvement is observed, consider starting replacement doses with hydrocortisone, always under medical supervision.

2️⃣ Antivirals: How Do They Help? Crucial in suppressing persistent viral replication, thus mitigating immune hyperactivity. Valtrex for herpesviruses such as EBV and Paxlovid for SARS-CoV-2.

3️⃣ DHEA supplementation if deficiency exists:
▪️ How Does It Help? DHEA is important for hormonal balance, especially when corticosteroid use inhibits ACTH production. It helps maintain energy and decrease the autoreactive T-cell response.

4️⃣ Antioxidants and Metabolic Precursors:
▪️ Vitamins (C, B-complex), NAC, ALA, SAM-e, Selenium:
* How do they help? Reduce oxidative stress, improve mitochondrial function and restore glutathione levels, thus supporting cellular recovery and immune function.

▪️ NMN (Nicotinamide Mononucleotide):

* How does it help? Restores NAD+ levels, crucial for antiviral activities and cellular health.

5️⃣ Glutamine:
* How Does It Help. Supports energy metabolism and immune function, especially during states of high immune demand.

6️⃣ Astragalus:
* How Does It Help? Reduces oxidative stress and has immunomodulatory properties that may enhance CD4 T-cell deficient immune response and prevent viral reactivation, especially of EBV. Astragalus has shown indications of reducing clotting, which could have potential benefits in conditions associated with microclot formation.

7️⃣ Protein and Creatine supplementation:
* How Do They Help? They maintain protein synthesis and prevent muscle breakdown, thus improving energy and physical recovery. Beware of creatine and protein supplements, as they do not suit everyone equally well, and may generate gastrointestinal problems.

8️⃣ Vitamin D:
* How Does it help? Reduces T-cell hyperactivation and improves insulin sensitivity, which may have additional benefits in inflammatory diseases and insulin resistance.

9️⃣ Melatonin:
* How Does It Help? Improves sleep, protects the central nervous system and reduces neuroinflammation and oxidative stress. It is essential not to sleep less than 8 hours, as in patients with hypocortisolism, lack of sleep can further destabilize cortisol production, worsen symptoms, destabilize circadian rhythms and reduce cortisol needed for awakening.

Antihistamines:
* How Do They Help? They reduce inflammation caused by histamine accumulation due to decreased DAO activity, decreasing Th2 response and improving allergies, food intolerances and fatigue.

1️⃣1️⃣ Nutrition:
* How Do They Help? These patients may tolerate less food and present food intolerances due to inflammation and oxidative stress, as a consequence of immune hyperactivation and low cortisol. The intestine is one of the tissues most affected by oxidative stress, especially during digestion, as this process generates free radicals that can damage intestinal cells. A diet rich in antioxidants is essential to neutralize these free radicals, mitigate tissue damage and improve food tolerance. It is therefore important to take antioxidant supplements during meals and avoid foods that generate more inflammatory load, such as those rich in histamine.

➡️ More information in our review article: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full


Dosage and timing of treatments
While many of these supplements may be familiar to most patients and some have even been tried before, the real key to this therapeutic approach lies in the precision of dosages and frequency of administration throughout the day to maintain stable blood levels. It is also critical to make these adjustments under proper medical supervision to ensure the long-term safety and efficacy of the treatment.


Expected Benefits:

Reduction of Inflammation and Oxidative Stress: Improving quality of life and daily energy.
Immune and Hormonal Regulation: Helping to stabilize immune and hormonal function.
Improving Clinical Symptoms: By addressing the root cause of immune and hormonal dysfunction, symptoms such as fatigue, pain and cognitive issues may decreas

To advance the scientific validation of these protocols, we are considering the possibility of conducting a clinical trial. We are currently seeking funding for this project, as we believe it is essential to demonstrate the efficacy of these treatments in a broader context. I also believe that, in order to advance as quickly as possible in the treatment of these pathologies, the collaboration of several centers testing these treatments is necessary. For that reason if any center/institution wants to do a joint study we are open to collaborate and receive funding.

Please, if you are taking these supplements and treatments and you are going to participate in any study of these diseases, I encourage you to communicate it to the responsible of the study. As they could change the results of the study. This is crucial to ensure the validity of the data and to avoid any bias that may mask the reality of these complex medical conditions. In addition, it is critical that these treatments and supplements be supervised by your physician.

Let's keep working together to advance the treatment of Long COVID, ME/CFS and post-vaccine syndromes! Thanks for reading this great thread!

Share all this information with other patients and physicians/researchers to improve the quality of life for these patients. Together we can move towards more effective treatments and a better understanding of these medical conditions.

I will be uploading more information related to this article in the coming weeks.

Attached is another thread where we explain the consequences and development of acquired immunodeficiency in these patients:

This article has been possible thanks to the research line funded by @PlzSolveCFS and Helpify, carried out at the @CIMA_unav of the @unav with the team of Dr. Bruno Paiva (@BrunoPaiva_UNAV). we deeply appreciate their support!

 

My impression was that AISA was an imaginary disease invented by Yehuda Schoenfeld.
Since there is no inflammation in ME/CFS I don't see much point in trying to link it to a non-0existent inflammatory syndrome.

 

Looking around a bit the paper that originated the term ASIA seems to be this one:

It doesn't look like it's open access so here is the table with the original proposed criteria:

It looks like the major criteria just represents a clinically defined syndrome that will obviously overlap quite a bit with ME/CFS (and the minor criteria are a bit of a muddle).

 

@Manuel, thank you for this paper. I think it draws together many threads. I had a question about the HLA genes though.

You point out that HLA genes are known to be correlated with ME/CFS:

You then talk about HLA-DR2 and paint a compelling picture of how it can cause CD4 overreaction and CD8 overreaction. This means it is possible to have autoimmunity while also failing to clear the pathogen.

My question though is how this is relevant. HLA-DR2 (including both forms HLA-DR15 and HLA-DR16) are not known to be correlated with ME/CFS.

Are you arguing by analogy? Or is there something I'm missing?

 

And so far, there is pretty good evidence for ME/CFS not being associated with MHC genes. The largest data set so far available showed no signal if I remember rightly. Some suggestions from the past did not hold up.

 

Is all immune activation inflammation?

 

A few things fit for me - HLA type, periods of hypocortisolism, post vaccine initiation (not necessarily prompter) but I have been diagnosed after covid a_Z vaccines and 36 yrs after start of fatigue with sarcoidosis. I have some suspicion of Lyme and my HLA is also consistent with post Lyme. I have also evidence of immune activation, though granuloma of sarcoid is the only direct evidence of what would be generally referred to as inflammation by medics. My symptomatic history overlaps with ME/CFS diagnosed but imo we still have the subgroup problem and though I would now get a diagnosis of sarcoid fatigue, until 2021 it would have been ME/CFS - to the point of giving me the useless in my case CBT/GET and if the signs of sarcoid fully remit and the "ME" does not whence? And I still don't know if I have PEM or exertion intolerance.
Perhaps these researchers have hit on sth relevant to a subgroup and possibly of some practical assistance to others. Now Sarcoid which is still active is being diagnosed as CFS as I posted elsewhere. Perhaps Julia Newton's idiopathic fatigue will be revived but CFS/ME as to cause is an idiopathic diagnosis , isn't it? (Not disregarding 2 day CPET but that is a process which has not yet been explained and imo not everyone in CFS/ME land will have it despite symptomatic consistency).

 

For proper science, you need to look at whether most things fit, or at least there isn't strong data that doesn't fit. Cherrypicking a few data points that do fit isn't science.

 

Passing a comment is not proper science but it may be helpful. There might be some "me toos" on this forum.
Passing a brief comment about cherry-picking is not science either, as I am sure you would concede.
My comment is brief and we could go thru my entire 39 year history to see if there might be a whole cherry tree of commonalities between my case and the proposed cohort/condition or rather not. I doubt we could reach a scientific standard of proof. But "scientifically proven" is not a synonym for true, nor for relevant or helpful. I hope my comment will be relevant and helpful to some on here.

 

Frontiers type journals are major purveyors of this sort of “research”. I don’t read anything that comes out of such journals because the signal to noise ratio just isn’t worth it. So much quackery out there. The only real immunological finding that I know of in ME/CFS is TGF beta and that’s not inflammatory if I recall correctly.

 

Has any role been found for TGF beta in promoting fatigue, since it is claimed here to play a role in sarcoidosis?

Immunohistochemical localization of transforming growth factor-beta 1 in the non-necrotizing granulomas of pulmonary sarcoidosis. | American Journal of Respiratory and Critical Care Medicine (atsjournals.org)

 

No. But ASIA is supposed to inflammatory.

To be honest, I don't want to go into detail but this stuff is about as close Qanon a immunology gets. It is not only garbage but garbage intended to manipulate the gullible.

The cherry picking comment was spot on. It is a waste of time looking for clues in similarities unless the whole picture fits together. You might as well say measles is like psoriasis.

 

IMO we are

I think the term inflammation is used when immune activation would be better and I have noticed you object to inflammation as a term in some contexts, leaving at times imo issues of immune activation unaddressed.

The cherry picking post I took as being addressed to me personally, as if my remarking on some commonalities between my own case and what is being claimed by Manuel et al was "cherry picking". I have dealt with that aspect in my response to Creekside. If Creekside's post was in fact intended to point out that any supposedly comprehensive assertion about ME/CFS has to fit the diagnosed group as a whole (is that really possible in our syndrome umbrella?) rather than some individuals in the diagnosed group, then I take the cherry picking phrase as fair, but even that does not abolish any truth in Manuel's position. Pseudo-science is imo sth. which is claimed to be science but is not and that is often based on cherry picking. Nevertheless, there may be truth in pseudo-science since "scientifically proven" and "true" are not synonyms.

Many of us are not trained scientists but patients. We do not do our own history scientifically but as historical account. For me to assert as science that I may have had sarcoid from 1985 or before, or it may have been Lyme or it may have been the old umbrella CFS/ME (umbrella being imo what the diagnosis produces), that my fatigue was this or that cytokine or whatever would indeed be pseudo-science involving cherry picking. But to note these as part of my history without further assertions is neither pseudo science nor cherry picking. It is just patient history not a point inviting a reprimanding tone from anyone. Perhaps the target of the original cherry picking remarks was in fact the researchers, which I may have misunderstood and which you may have now clarified.

 

Other forms of immune activation are unaddressed by inflammation, of course, but I am only too happy to invoke them in all sorts of ways in disease. Complement activation in the bloodstream is anti-inflammatory for instance. The response a vaccine prevents later inflammation. But when people through around terms like immune activation as in ASIA it is just a word salad with no defined mechanism.

I appreciate it is difficult for the nonsxientist because in immunology most of the popular received wisdom about specific diseases published by most research groups is seriously flawed or plain wrong. But at least on S4ME we usually end up unpicking what matters. The vast majority of things don't tie together much. When they do, in my lab experience it is mind blowing just how perfectly everything fits - as I suppose it must if it the reality!!

 

My comment about cherrypicking was a response to "A few things fit for me". I expect that if you looked at the descriptions of all known diseases, you'd find that "a few things about your ME" would fit thousands or maybe tens of thousand of other diseases. When you include more than just a few things, the correlations drop, and when you include all the negative clinical results, you're left with only a few, one of which is ME. The same applies to hypotheses about ME: one might fit a few things about your experience, until you include more data and one or more of those fail the hypothesis.

It wasn't an attack on you personally, just that "fitting a few points" doesn't have much value, especially for a hypothesis that is complex and lacking in easy-to-test components.