Since they finally seem to have their first paper published soon, this time for real, hopefully, I'd like to discuss this latest update.
Their main point for the symptomology is angiogenesis and vasodilation. This also happens in MCAS and CFS/ME, though. This is why histamine-induced symptoms are dominantly expressed as headache . Endothelial barrier inflammation and dysfunction isn't new to CFS/ME either [2, 3, 4, 5].
They also elaborate on the monocyte polarization and monocyte migration. This also happens in MS and Autoimmune Encephalitis (AE) in one way or another [6, 7, 8]. Most importantly, it's not new to the CFS/ME etiology either [9, 10, 11]. The real question is why do the monocytes of CFS/ME and Post-COVID patients respond differently? As Morris et al. elaborate , this is mediated by miRNAs, consistent with the findings of Prusty and other research teams [5, 12].
From my understanding, it is very well possible that latent and abortive viral activity reprogrammed the monocytes, or in generalized terms, causes an overall immune dysfunction, which then leads to a defective immune response to the SARS-CoV-2 virus just as to other viruses as well. SARS-CoV-2 is just the ideal trigger because of its high receptor affinity to endothelial cells. So far, I don't see any outstanding difference to CFS/ME yet.
Dr. Patterson says he is looking for a causal treatment, but all he describes so far is the symptomatic mechanism. Don't get me wrong, this is just as important to understanding the disease, but his treatment focuses on the immunology that causes the symptomology that he assumes. It's just an assumption that the whole condition is defined by endothelial, vascular, and monocyte dysfunction. He says he doesn't believe that macrophages participate, referring to macrophage biopsies from the gut, but I think it's more interesting to look at macrophage migration at the blood-brain barrier (BBB).
To be fair, he also implements Ivermectin into his protocols. Molecular docking simulations show that Ivermectin might be a potent spike protein antagonist at the ACE2 receptor . According to the work of Patterson, the spike protein is at least co-responsible for the pathology in that the ill-polarized monocytes try to present spike protein antigens. Ivermectin might help to remove the spike proteins from being processed, thereby reversing at least the triggering participation of the SARS-CoV-2 in the overall pathophysiology.
This also explains why some vaccines might trigger a similar condition. Monocyte antigen presentation can happen whenever the innate immune system participates in the immune response. When, for example, miRNAs dysregulate the innate immune system, it doesn't matter what antigens would have to be presented, it would always lead to the same result on a cellular level. The only difference is the expression of the respective pathogen in the different tissue types/organs, altering the manifestation of the disease.
Now, we also know that long haulers produce antibodies quite rarely. Hence, it isn't surprising that the innate immune system does all the work since COVID-19, the hospitalization disease, doesn't really break out in these patients. The innate immune system is quicker than the adaptive immune system. Antibody production takes a lot of time until it participates in the defense against SARS-CoV-2.
Fortunately, there is a possible solution to get the adaptive immune system involved, namely the Novavax vaccine. As soon as the adaptive immune system is able to detect the spike proteins, it's possible that the monocyte pathophysiology calms down. However, it's possible that long haulers might have a poorer response to Novavax in terms of efficacy, or that the spike proteins of the vaccine also participate in the pathology somehow, although this seems unlikely because the spike proteins are pre-fused and can not affect monocyte antigen presentation directly as long as they don't interact with cells that are targeted by monocytes.
Apparently, Dr. Patterson and his colleagues are also aware of the issue with the cell cycle modulation, which by the way is also a target of miRNAs, as well as a target of viral proteins. He thinks his treatment also works in that regard because the symptoms and macrophage pathology resolves. But this doesn't mean that the monocytes are really sent into apoptosis. I'm not sure if the used treatments are cell-cycle modulators. Regardless, if miRNAs or other viral proteins participate in the etiology, the root cause will not be resolved but only suppressed as long as spike proteins and viral immune modulators circulate. I really hope that they will add a proper cell cycle therapy to their protocol.
The long hauler index is a good correlator to the symptoms and the control of the progression of symptoms, but from my perspective, there is no evidence that this actually is a correlator for the root causality of the long hauler disease. I don't want to overcomplicate things to genetic predisposition, but I think it's too early to generalize everything down to this index.
He also mentions that they couldn't find viral RNA, just viral protein. But where does it come from when cells aren't productively infected (anymore)? This is just a possibility, but it might be worth looking into the transcription of SARS-CoV-2 dsRNA into human DNA. This isn't particularly new to the SARS-CoV-2. DNA viruses can convert into RNA, ssRNA viruses like SARS-CoV-2 can convert into dsRNA and transcribe into DNA [14, 15, 16]. What miRNA can do, we don't even have a full idea yet. Maybe it's (partially) human DNA that produces viral proteins. In this case, targeted cell cycle therapy would also help in combination with a therapy that shuts down all other viral pathology.
He also projects his work on other diseases like Lyme. Chronic treatment-resistant Lyme is an HLA-DR-mediated disease. Genotypes can be responsible for dysfunctional or pathogen-disruptable antigen presentation/synthesis. Reverting the monocyte overreaction doesn't eliminate Lyme residues. It doesn't fix the pathogen-specific response. It's more like a specific immune suppression that improves the quality of life, but with unknown risks for relapses. We've seen this plenty of times with CFS/ME case reports, where it got worse after a certain period of time. I think corticosteroids are a typical example of this, improving symptoms for a certain period, and a severe relapse later.
This isn't intended to decry the work of Dr. Patterson and his colleagues. It's good work and hopefully, these unresolved questions of mine will eventually be resolved. He seems to be empathically engaged with the topic, this is something I'd hope to see more frequently in the medical community.
- Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo (2015) [10.1371/journal.pone.0132367]
- Large and small artery endothelial dysfunction in chronic fatigue syndrome (2012) [10.1016/j.ijcard.2011.10.030]
- Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study (2021) [10.3389/fmed.2021.642710]
- Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (2020) [10.1002/ehf2.12633]
- Altered endothelial dysfunction-related miRs in plasma from ME/CFS patients (2021) [10.1038/s41598-021-89834-9]
- MOSPD2 is a therapeutic target for the treatment of CNS inflammation (2020) [10.1111/cei.13448]
- Multiple Sclerosis Treatments Affect Monocyte-Derived Microvesicle Production (2017) [10.3389/fneur.2017.00422]
- NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis (2012) [10.1073/pnas.1201836109]
- The role of Dendritic Cells and Monocytes in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (2013) [10.3389/conf.fimmu.2013.02.01010]
- In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling (2021) [10.3390/proteomes9010006]
- Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop? (2019) [10.1007/s11011-019-0388-6]
- Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2020) [10.4049/immunohorizons.2000006]
- Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2 (2020) [10.21873/invivo.12134]
- SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome (2020) [10.1101/2020.12.12.422516]
- SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial-derived cells and cardiomyocytes (2021) [10.1073/pnas.2022643118]
- Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues (2021) [10.1073/pnas.2105968118]