“We have a huge problem and a major crisis on our hands.” Avindra Nath – on long COVID – at the conference
“I think the tools we’ve applied to study ME/CFS can now easily be applied to long COVID as well. And vice versa. What we’ve learned on long COVID is going to benefit us in ME/CFS,” Nath – Live Science
(This summary was taken from notes).
Dr. Avindra Nath gave the keynote talk at the 2021 IACFS/ME conference. Nath leads the clinical arm of the National Institute of Neurological Disorders and Stroke (NINDS). He’s been steeped in the central nervous system effects of post-viral disorders for decades and it shows.
The truth is – and Dr. Nath has referred to this before – that we’ve had a huge problem on our hands for quite a while. In a recent paper, Nath asserted that “Undiagnosed neuroinflammatory diseases carry a huge burden with devastating consequences”, and decried how unprepared the medical system is for a virus that affects the central nervous system. He called COVID-19 a “crisis for neurology”.
On the other hand, neurologists – perhaps the most resistant of all specialists to ME/CFS – have been something of a crisis for ME/CFS patients for a long time. It’s good to see a respected and influential neuroscientist fully embrace chronic fatigue syndrome (ME/CFS) and long COVID.
The “crisis” is not just about ME/CFS – it also concerns all the other post-infectious illnesses that have been virtually ignored by the research community for decades. The SARS-CoV-2 virus is simply demonstrating in spades what’s been known and ignored for years: that infections can, even after they’ve been “resolved”, have severe long-term consequences. Nor is it just the post-infectious aspect. I’ve been told that the NIH has put pathogen research on the back burner for years as well. Now that we’re seeing COVID-19 spin-off numerous post-infectious conditions, perhaps that will change.
Nath referred to a fascinating paper by Taquet which demonstrates: a) the many different effects infections can have; (b) how dangerous the coronavirus is; and (c) the kind of type of illuminating research that is pouring into the long-COVID field.
Taquet compared the neurological and psychiatric records of 236,000 survivors of COVID-19 to people who had come down with influenza and other respiratory diseases. The study showed that the coronavirus produces the most complications, influenza is next, and then come other respiratory infections.
The huge study validated the idea the infections, even after they are resolved, can have long-term consequences. That was eye-opening but what was really startling was how much more apt the coronavirus was to produce complications even compared to the flu. The image below compares some of the neurological complications produced by the coronavirus (red line) and influenza (blue line).
Note that while the rate of psychiatric disorders is pretty similar in the COVID-19 and influenza patients, the rate of muscle disease jumps up dramatically in COVID-19 patients.
With the first tranche of the NIH-funded long-COVID studies focused on large cohorts, we should be seeing many studies like this, including those that cover more complications. We’ll be looking to see what the prevalence of ME/CFS, FM, IBS, POTS, EDS, etc. is over time, but it’ll also be fascinating to see if the rates of autoimmune disorders like multiple sclerosis, Sjogren’s Syndrome, and lupus increase as well. We should also hopefully be able to see if different infections produce different post-infectious states. All this data should be in the electronic medical records.
Nath then shared an email from the husband of a formerly healthy mother who took her life a year after long COVID left her in enormous pain and unable to sleep. It’s remarkable that in this day and age our medical system had nothing to offer her. (Hopefully, the NIH’s HEAL effort – which is designed to produce better pain drugs – will help.)
Nath believes that long COVID is probably caused by either immune activation and/or viral persistence.
The dysautonomia that’s been showing up is likely due to damage to the endothelial cells lining the blood vessels which control blood flows and inflammation, sympathetic nervous system activation, and low blood volume.
The fact that plasma exchange and steroids can really help some patients indicates the role the immune system must be playing. Nath’s description of what appears to be happening in the immune system was a highlight for me. I’ve never heard the immune situation in long COVID or ME/CFS described in the way he did, but it appears to fit both diseases.
Nath reported that a technique called “single-cell sequencing” found “extremely aggressive” monocytes in the cerebral spinal fluid of COVID-19 patients with neurological issues.
Nath reported that the T-cells appeared to be exhausted. (Impaired T-cell metabolism has been found in ME/CFS). With the adaptive arm of the immune response hurting, the immune system turned to its early appearing innate arm to help out. The problem with that is that the innate arm of the immune response is like a bludgeon compared with the fine-tuned responses (antibodies, T-cell clones). Consisting of mast cells, monocytes and macrophages, dendritic cells, the complement system, and neutrophils, the innate arm produces a ton of inflammation and is hard to turn off once it gets going.
The use of the single-cell sequencing technique highlights another benefit from the large amount of funding going into COVID research. Besides the huge studies we’re going to be seeing, we’re likely going to see a lot of cutting-edge technology being brought to bear on long COVID.
Instead of examining a variety of cells types such as PBMCs at once, single-cell sequencing involves assessing individual cells using “optimized next-generation sequencing (NGS) technologies”. A PubMed search didn’t bring up any instances of “single-cell sequencing” in ME/CFS.
Vascular injury is certainly occurring in COVID: congested blood vessels, microhemorrhages, white hyperintensities (also found in ME/CFS) all indicate the blood vessels are affected. Nath has found three different types of vascular injury in COVID, and focused on the brainstem, a brain organ that has shown up in spades in ME/CFS.
The leaky blood vessels Nath found in the brains of COVID patients. His explanation of how that occurred made a new connection. Nath’s discovery of activated blood platelets touching the endothelial cells lining the blood vessels suggested that endothelial cells had activated the platelets. That’s interesting, as Bindu Paul and colleagues proposed that mitochondrial damage to the endothelial cells plays a major role in long COVID and ME/CFS. Once those platelets are activated, they can produce inflammation and blood clotting. (Nath has yet to find virus in the central nervous system and doesn’t believe the virus is present).
As only a neuroscientist could, Nath then marveled at a crystal-clear picture of the brainstem in COVID that had been produced. If my notes are correct, the brainstem shot suggested microglial activation was causing the loss of neurons there. Here, again, we have another potential connection between COVID and ME/CFS, as both the microglia and the brainstem are of great interest in ME/CFS.
When it came to potential treatments, Nath again veered into ME/CFS territory. After stating that antivirals might be a possibility, Nath suggested an immune treatment regimen that has been discussed (but perhaps not implemented) in ME/CFS: you knock the innate immune system down and pump the adaptive immune system (T-cells and interferon response) at the same time. One of the reasons that this treatment approach has not been taken in ME/CFS may be because of the difficulty physicians have in justifying it, but with the amount of research going into long COVID, the studies will show up that will allow that to happen in long COVID, and eventually in ME/CFS.
Nath then finished up fairly early in the session, which was good, as the lengthy question and answer period was perhaps the most interesting part of it. It was an interesting section as Nath showed no compunction about shooting down a number of sacred cows…
Q & A Period
- Nath called long COVID “a huge problem and a major crisis”.
- A huge UK study found that COVID-19, influenza, and other respiratory infections all produced long-lasting complications in some, with COVID-19 producing more than the flu, and the flu producing more than respiratory infections. We should see many more studies of this size and ilk over time.
- Nath believes immune activation or viral persistence is likely the cause of long COVID. The coronavirus could be persisting in the stomach lining or elsewhere, and it could be pumping out proteins that are activating the immune system.
- Citing a finding of “extremely aggressive monocytes”, Nath suggested that T-cell exhaustion may be causing the immune system to compensate by jacking up the efforts of the early acting, highly inflammatory, innate immune system. It may be necessary to enhance the later-acting adaptive side of the immune system, while knocking down the innate immune system.
- Congested blood vessels, microhemorrhages, and white hyperintensities (also found in ME/CFS) all indicate that a complex problem involving the blood vessels is present. Nath believes damaged endothelial cells lining the blood vessels are activating the blood platelets, which then produce inflammation.
- While the impact on the brain can be widespread, Nath focused particular attention on the brainstem – a brain organ of interest in ME/CFS as well. Microglial activation there appears to be damaging the neurons. Nath has been unable to find evidence of virus in the brain.
- During the Q & A, Nath proposed that because of the vanishingly small amount of protein found in them, the coronavirus vaccines are far safer than the virus itself. He suggested that people who fare poorly with the vaccines would likely have done far worse with the virus.
- When asked if the glymphatic system, EBV reactivation, epigenetic alterations or autoantibodies were involved in long COVID, Nath said all of those are commonly found in central nervous system diseases. He warned about giving too much significance to EBV reactivation or the presence of autoantibodies.
- The ME/CFS Intramural Study was closed with the advent of COVID-19, and no more patients will go through the study. They are analyzing the results of the study now. The results of that study will be compared with the results of the long-COVID study, which is employing ME/CFS-like patients.
Are mast cells a major player? Dr. Peter Rowe noted that mast cells are key drivers of innate immune response and reported that he was regularly finding high histamine levels in his long-COVID patients. Nath acknowledged that he doesn’t know a lot about mast cells but agreed it is an important area.
Is epigenetics behind long COVID? One person asked if epigenetic changes were causing long COVID? Nath agreed there probably is a host genetic component but that it’s polygenetic; i.e. it’s spread across many genes, and we need more advances in genetics to get the full picture. He also asserted that epigenetic changes are expected as epigenetics plays a role in all diseases.
Is the glymphatic system involved? Ray Perrin got a similar answer when he asked whether the glymphatic system was involved in long COVID. Nath said yes, but that glymphatic problems have shown up in every central nervous system disease.
What’s happened with the intramural ME/CFS study? I was itching to get some results from the intramural ME/CFS study, and so asked about that. Nath gave the (somewhat) disappointing, but not surprising, news. When COVID-19 came along, recruitment into the ME/CFS study stopped – permanently. Nath said that they’d put a “decent number” of patients through the study, and that the investigators were meeting weekly to analyze it. They hope to produce one large publication, followed by a series of smaller ones.
In response to an email, Nath reported that the ME/CFS intramural study is living on in the form of an intramural study of long-COVID patients with ME/CFS symptoms. The results of that study will then be compared with those of the ME/CFS study.
What about false recoveries? Some patients recover completely, and then complain of symptoms weeks later. Why is that? Nath, who had a great deal of experience with post-infectious diseases, suggested a couple of possibilities: the virus might have gotten knocked down but was still present, and was gradually building up and driving an immune system reaction… or the virus was knocked down and it took a while for autoantigens and other parts of the immune system to act up.
Are viruses present in the brain lesions? Dr. Chia wanted to know if viral RNA proteins were present in the brain lesions Nath assessed. Nath clearly tried hard – he used multiple methods to look for pathogens, and failed to find any.
Could the coronavirus be persisting in the gut? Could the virus be present in the gut lining? Nath loved this question. Absolutely the gut could be a reservoir for pathogens.
Is EBV reactivation a big deal? A doctor reported that he has 3 patients with EBV reactivation. Nath called the EBV situation complex but noted that every neuroinflammatory disease causes EBV reactivation. At least once a week he gets a notice that a spinal tap has found EBV in it. It’s very hard to sort out whether the EBV reactivation is significant or not. What we really need is a drug that blocks EBV and then see what happens.
Could virus-related proteins be causing an immune response in long COVID? Nath said this question was music to his ears. Even if HIV has been knocked down, HIV related proteins are showing up. The same is true of measles. While Nath didn’t mention it, similar hypotheses have been advanced regarding EBV, enterovirus and HHV-6 proteins.
Are autoantibodies a big deal in long COVID? Nath was not high on autoantibodies. He said you have to be very careful about autoantibodies. You find hordes of autoantibodies in all central nervous system diseases, most of which are not causing any problems.
Update: Nath recently said: