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?
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.
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.
Hypocortisolemia: We highlight the decrease in ACTH production and its impact on immune function and clinical symptoms, establishing a direct link with pituitary dysfunction.
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.
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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:
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.
Autoimmunity Against the Adenohypophysis:
* Both conditions can lead to autoimmune inflammation of the adenohypophysis (autoimmune hypophysitis), resulting in hormonal dysfunction, especially ACTH production.
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?
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.
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.
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:
Hydrocortisone Maintenance:
Maintain hydrocortisone therapy at appropriate doses to control symptoms and avoid adrenal insufficiency.
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).
Glutamine:
Astragalus:
Protein and Creatine supplementation:
Vitamin D:
Melatonin:
