Three years after the pandemic had destroyed any attempt to get back to the East Coast and Washington, DC, I was back in Avindra Nath’s office at the NIH’s huge Clinical Center.
The world’s largest hospital that’s devoted entirely to clinical research, the Clinical Center generally has 1,500 researchers packed away working on research projects – and it showed. I quickly got lost in the seemingly endless maze of offices and was beginning to panic (not late again!), but someone took pity on me and walked me down to Nath’s office.
At 11:03 AM, apologizing for being late – he’s clearly committed to being on time – Nath popped in and we sat down in a nearby conference room. Other than the fact that I was masked and he was masked – and I wasn’t late and soaked this time – everything seemed pretty normal.
The Chronic Fatigue Syndrome (ME/CFS) Intramural Study
Nath has been the Clinical Director of the work the National Institute for Neurological Diseases and Stroke (NINDS) does at the Clinical Center for over ten years.
He’s been running the massive NIH-funded intramural ME/CFS study. The study, which painstakingly assessed its participants to ensure they had an infection-triggered case of chronic fatigue syndrome (ME/CFS), involved two week-long stays at the hospital.
While the study didn’t have all that many participants, its scope – using exercise studies to assess the immune system, brain, autonomic nervous system functioning, and many others – was large, indeed. The intense initial examination – which took up a week at the facility – was designed to ensure that only people with a post-infectious onset of ME/CFS were in the study. Another week of testing followed later. That, in itself, made it a unique study in the annals of ME/CFS research.
So did its goal. The intramural study – created entirely by and within the NIH – was produced with the implicit promise that if the study found something, the NIH would pursue it. That promise made it potentially the most important study in the history of ME/CFS.
As it did with so many things, the coronavirus pandemic upended the study. It put an abrupt end to the ME/CFS study, but what it took away on one hand, it gave with another as it also fostered a similar long-COVID study. Since long COVID appears to closely resemble ME/CFS, the study, in a sense, went on – just with another facet of ME/CFS – the long-COVID facet.
Still, it’s ME/CFS at this point that needs the funding, and the early ending of an already small study was concerning. I asked Nath how the early end of the ME/CFS study had affected it?
Nath replied that the sample size was smaller than what he would have wanted but that they’d studied everyone extensively and collected a lot of data on them. The studies were probably going to get critiqued in the journals because of their small sample size, but the goal of the project – to find further avenues for research – was accomplished. Nath said, “While we may not be able to make conclusive statements, we can certainly say that these are very important things to pursue in other studies.”
That was huge. As Nath said, the study was never designed to solve ME/CFS – it was designed to set a framework for future funding, and that was accomplished.
This was a big project that ended up requiring many different disciplines which had never worked together to work together. Ultimately, Nath created five different research groups to analyze the data.
As the data came in, he brought the groups together to take a crack at it. As each group interrogated their data in relation to the other groups’ data, new questions came up. Should we dig deeper into this? Should we analyze these samples differently? This kind of iterative multidisciplinary process basically mimicked what goes on in the body as different systems interact with each other. It made total sense and one wishes more projects like it were underway.
It sounded like such a complex process that I asked him if he’d ever done anything like this before? He laughed and said no. It was a lot of fun, and a lot of learning took place, but it also took quite a while.
Each group has written up its own section which is being amalgamated into a big paper that is pretty close to being submitted. There won’t be just one manuscript, though. Some of the researchers got excited enough about their findings to write papers on their own. Those smaller papers are being held back until the main one is published.
I remarked that it sounded like the project has triggered quite a bit of interest (???). Nath said it’s triggered “a lot of interest”, that he expects many papers to come out of the study, and thinks the results are going to be “fascinating”.
The long-COVID study that’s underway is similar to the ME/CFS study: the huge questionnaires, the intense screening process, and the several weeks stay at the hospital – they were all retained in the new study. So, by the way, are the research teams that are now comfortable working together in this new multidisciplinary environment.
A few things will be different – a more intense focus is being given to coagulation and the metabolic chamber is probably going by the wayside. It was so difficult to get access to the metabolic chamber that it considerably slowed the study down and wasn’t revealing enough in itself to justify the wait.
Always hoping for good news, I asked (fingers crossed) if, in his experience, long COVID had sparked more interest in ME/CFS. He said it had sparked “huge interest…Everybody knows somebody who has had long COVID and is asking “What can I do to make a difference? The self-motivation factor is extremely high and everyone understands there is overlap with ME/CFS. If you study one, you’re going to benefit the other.”
I asked how close the two diseases were. Thus far, Nath has found that they’re mostly the same but not entirely. Besides the fact that some people with long COVID have organ damage, there appears to be more microvascular disease, blood clots, and blood vessel problems in long COVID. There also appears to be less PEM.
I asked him if anything had surprised him about ME/CFS? He said different groups in the study would probably tell you they were quite surprised to find what they did. From an immunological point of view, he found immune activation. How and why it’s present is unclear, though.
Immune activation can be present without being the culprit in a disease. Nath noted that a subset of individuals with ALS, for instance, have immune activation, but halting it doesn’t stop the progression of the disease. It’s a secondary effect of the disease and something else is driving it. The immune activation he’s found could be driving ME/CFS, could be a secondary effect of the disease, or it could even be protective.
Nath noted how important central nervous system problems are in long COVID and ME/CFS. While the early symptoms like food and smell problems get a lot of press, the long-term consequences, the ones that are disabling, the ones that allow you to function in society – are mostly neurological.
(A recent study found that a COVID-19 infection is increasing the risk of a vast array of neurological disorders, including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (e.g. migraine and seizures), movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain–Barré syndrome, and encephalitis or encephalopathy.)
In fact, Nath is now engaged in a two-part neurological study of long COVID, the second part of which involves a clinical trial in which high-dose steroids, IVIG, or placebo will be given to see how these different immune factors affect the immune system.
Nath’s done two brain autopsy papers of COVID-19 patients. The second brain autopsy paper found blood vessel damage, protein leakage into the brain, immune complex formation, microglial activation (neuroinflammation), and activation of the classical complement pathway.
Nath believed that antibody attacks on the endothelial cells lining the blood vessels were probably the inciting trigger. Next came platelet activation and leaky blood vessels. Those macrophages, though, were a problem. If they enter the brain, they are like unwanted guests – they never leave. If they remain activated, they can damage the myelin covering the neurons for a long time.
(Jarred Younger is studying immune cell infiltration into the brain in ME/CFS. Nath wondered whether something similar could be happening in long COVID and ME/CFS, and noted that new and better radioligands that can more definitively determine if activated microglia are present have recently been developed (the older ones are not very effective). He was “very eager” to use them in long COVID and was talking to people at Johns Hopkins to get that done.
That brought up what to do if immune activation is driving these diseases. Nath noted that researchers at long-COVID conferences are already talking about trying immunotherapies. (Dr. Klimas is a bit ahead of the game here – she’s has been wanting to use immunotherapies in ME/CFS for at least a decade.) They’re tricky, though, and Nath warned that they have to be done in the context of clinical trials – doctors should not be trying them as they can do more harm than good if you’re not careful.
- Three years after the pandemic interrupted any attempts to get back to DC and see Avindra Nath, I was back. (This time I was on time. (lol)).
- Nath is finishing up the 5-year (but interrupted) NIH Intramural ME/CFS study, which included two week-long stays at the facility, exercise testing, immune testing, brain imaging, etc.
- The study was truncated by the pandemic, but Nath said mounds of data were gathered and the goal of the study – to uncover areas for the NIH to study – was met.
- The study was so wide-ranging the five different research teams participated and ultimately collaborated with each. One large paper is almost done, and Nath expects many smaller papers to come out of it. He said the study had sparked “huge interest” and called the results “fascinating”.
- Nath, an immunologist, said he found evidence of immune activation but could not say whether it was driving the disease, was an add-on effect, or if it might be protective.
- His COVID-19 brain autopsy work, though, suggested that antibodies were attracting immune cells and platelets to the endothelial cells lining the blood vessels and causing blood vessel leaks which were being mopped up by macrophages.
- The trouble is that macrophages are not supposed to be in the brain, and once they’re there, they behave like unwanted guests: i.e. they stick around.
- If macrophages are the issue – and some other studies suggest they might be – Nath noted that a variety of immunotherapies (IVIG; anti-TNF-a, IL-1, IL-6, or JakStat inhibitors) could be helpful. These types of drugs are already being discussed with regard to long COVID in conferences.
- Recent strains of the virus are less virulent, but more immune evasive and stick around longer in the body. In the long term, it’s possible they cause more damage including things like long COVID.
- Nath called diseases like ME/CFS, long COVID, fibromyalgia, POTS, post-Lyme Syndrome, Gulf War Illness, and Sick Building Syndrome the “mysteries of medicine” and believes that “if you solve one – you’ll solve them all.”
- He proposed that “the best way to get at any one of them is to pick one and throw everything at it and solve it. Don’t jump around studying a little bit of this one and a little bit of that one – pick one and dig into it. You’ll probably find that what you found there is applicable to all these other diseases.”
- Nath believes the long-COVID field is exploding and that over the next year we’re going to learn a lot.
- He’s not concerned about the ability of the ME/CFS field to integrate the findings that are sure to come from long COVID into it stating “It’s all going to get integrated….Even if you wanted to, you couldn’t separate them. There’s no reason to fear.”
After I asked whether different strains of the coronavirus might be producing different kinds of long COVID, Nath noted that recent strains of the virus are better able to evade the immune system, appear to be more persistent in the body, and may be less virulent but persist longer. This is actually a pretty common outcome of viruses as they learn to adapt to the body. It’s possible, though, that they may actually cause more long-term damage – something he wonders about with long COVID.
Then there’s the question of viral persistence. Could a persistent virus or part of a virus be driving long COVID or ME/CFS? Nath didn’t know but noted that we all have a lot of viruses in us (EBV, CMV, chickenpox, and others) which usually don’t cause any problems. If you become immune suppressed, on the other hand, they can cause bad things.
The Mysteries of Medicine… Solved?
Nath called diseases like ME/CFS, long COVID, fibromyalgia, POTS, post-Lyme Syndrome, Gulf War Illness, and Sick Building Syndrome the “mysteries of medicine” and believes there’s a huge overlap between all of them. His guess was “if you solve one – you’ll solve them all.”
He proposed that “the best way to get at any one of them is to pick one and throw everything at it and solve it. That’s the key thing. Don’t jump around studying a little bit of this one and a little bit of that one – pick one and dig into it. You’ll probably find that what you found there is applicable to all these other diseases.”
Let’s hope Nath is right – that’s precisely what’s happening with long COVID.
That’s why, he said, researchers sometimes study really rare diseases or rare forms of diseases. A single family with an unusual form of a disease could hold the key that unlocks the disease for everyone else.
For instance, there was a case report of a family whose members – except for one member – developed Alzheimer’s at a young age. A rare mutation was found in every member of the family – even the member who remained healthy – that turned on Alzheimer’s early. The healthy member, though, had a mutation that impeded the progress of Alzheimer’s – and that mutation presented a possible key to treating Alzheimer’s.
I asked him how much he thought we’ll know about long COVID in a year? He said:
“I think we’re going to know a lot. There are so many labs working simultaneously and the NIH is dumping a lot of money into the RECOVER Initiative, but they’re not the only source. There’s private money, philanthropy, industry – all kinds of ways people are doing things. It’s just exploding.”
The ME/CFS field is so small, though. Was he concerned about the ability of the ME/CFS field to integrate the long-COVID findings into it?
He wasn’t – stating, “It’s all going to get integrated….Even if you wanted to, you couldn’t separate them. There’s no reason to fear.”
That was good to hear, and that was a good note to end the interview on. It’s going to be fascinating to see what Nath and his multi-disciplinary team found. Plus, when his long-COVID project wraps up, Nath is also going to be able to give us the most detailed and wide-ranging comparison between ME/CFS and long COVID yet.
On our end, it will be critical to ensure that the NIH responds appropriately. Thus far, the NIH has been acting as if ME/CFS was somehow divorced from long COVID. No new funding opportunities have been announced and the NIH is sticking with the 3 rather meagerly funded NIH ME/CFS research centers.
Since the goal of the project is to uncover areas to concentrate on, that should change. The intramural ME/CFS study, though, was Francis Collins’s baby and he’s not there anymore. It was great to see Nath’s confidence that long-COVID results are going to filter down to ME/CFS and we are going to need to have the NIH honor its promise to us and devote significant new resources to ME/CFS.
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