(Brian Vastag comes full circle. A former employee of the NIH, Vastag’s Washington Post letter to NIH Director Francis Collins “I’m disabled. Can NIH spare a few dimes?“, in conjunction with the recently published IOM and NIH Pathways to Prevention reports, and the actions of many advocates cohered to give ME/CFS its first big boost in research funding in years.
Three ME/CFS research centers were established and an intramural study that Avindra Nath called the most intense effort he’s been involved in began. Patient #4 in that study, Brian first recently posted his experiences of the study and his thoughts on what lies ahead on a thread on the social media site Mastodon. Thanks to Brian for allowing Health Rising to share his story as we await the first publications of this potentially epochal study. Cort)
Six years ago, I returned to NIH, where I started my career as a science writer, to be a patient in an ambitious study to understand post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
The study included 30+ researchers & substudies & was a fishing expedition to understand what goes wrong to make us so sick (like bedbound-for-years sick).
NEWS: The study’s findings have FINALLY been submitted for publication.
The study began after I wrote to then-NIH Director Francis Collins, whom I had talked to in my job as a science reporter at the Washington Post, imploring him to invest in understanding ME/CFS, which has been neglected for decades. I also knew other top administrators at NIH and so decided to use my connections to try to get some movement.
Collins, to his credit, emailed me and said he would move fast. This was in 2015. And he kept his word. He gathered some top clinicians at NIH and told them to design an intramural study – meaning it would take place on the NIH campus in Bethesda, Md. – to try to figure out what goes so wrong in the disease. Collins chose neurovirologist Avindra Nath (pictured with me above) to be the principal investigator. Nath is the head of clinical neurology at the NIH Clinical Center.
A 2015 Institute of Medicine report “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” had reaffirmed that ME/CFS was a biological, not psychological, disorder, and there had been other pressures on Collins to act. So he moved responsibility for ME/CFS out of the small and under-funded Office of Women’s Health over to the National Institute of Neurological Disorders and Stroke, a more appropriate home.
While the protocol for the study was designed and approved in a month – very fast for NIH – it took almost a year to stand up the study, hire some support staff, and begin recruiting patients and healthy volunteers as controls.
As compiled by advocacy group MEAction, the first aim of the study, during visit 1 for patients, was “**To define the clinical phenotype.”** Via: History and physical examination and systemic assessment Neurological assessment Neurocognitive assessment Psychiatric evaluation Pain/headache evaluation Infectious disease and rheumatologic evaluation by specialists Neuroendocrine evaluation Fatigue testing, exercise capacity https://me-pedia.org/wiki/NIH_Post-Infectious_ME/CFS_Study
Defining the clinical phenotype – As compiled by the advocacy group MEAction, the first aim of the study, during visit 1 for patients, was “To define the clinical phenotype” via:
- History and physical examination and systemic assessment
- Neurological assessment
- Neurocognitive assessment
- Psychiatric evaluation
- Pain/headache evaluation
- Infectious disease and rheumatologic evaluation by specialists
- Neuroendocrine evaluation
- Fatigue testing, exercise capacity
Plumbing the biology of post-exertional malaise – During the second visit, patients were evaluated pre- and post-exercise, to try to plumb the biology of post-exertional malaise – the phenomenon where exertion makes us sicker, using:
- Functional MRI
- Metabolic studies
- Transcranial magnetic stimulation
- Autonomic function
- The study also added skin-punch biopsies, to evaluate small-fiber neuropathy, & muscle biopsies.
Immunology – “The third aim of this study is to conduct a detailed immunological study in blood as well as cerebrospinal fluid including a screen for autoantibodies…. We will also fully explore the gut and oral microbiome and apply proteomics and metabolomics approaches to the cerebrospinal fluid. Studies for aim 3 include:
- Cytokine & chemokine profile in cerebrospinal fluid and blood; after T cell stimulation in culture
- Flow cytometry
- B cell and T cell cloning and T cell antigen receptor sequencing
- Immunoglobulin profile
- Autoantibodies directed against brain antigens
- Cerebrospinal fluid proteomics and metabolomics
- Gut and oral microbiome
- Serum tryptase
- Viral discovery in spinal fluid
Reproducing the disease phenotype – The fourth aim was to see if the disease phenotype could be reproduced ex vivo (outside the body). NIH was to:
- Do metabolic studies on neurons made from patient blood stem cells
- Study humanized mice made from patient stem cells
- To determine if cerebrospinal fluid or antibodies injected in brains of rodents or humanized mice generated with cells from patients can lead to fatigue or behavioral abnormalities.
So, there might be a mouse made from ME running around NIH.
“If these experimental systems are able to reproduce the clinical or biological abnormalities seen in these patients, it would be a major step towards identifying the cause and the pathophysiology of the illness and for developing a variety of treatment approaches to these patients.” – Dr. Nath, principle investigator.
I was patient #4 when I arrived in April 2017. The study was grueling. I wore an ECG cap for a sleep study (I didn’t get much sleep); had a difficult spinal tap; donated 10 million blood stem cells; had 29 vials of blood taken in one go (fun morning!); took extensive cognitive exams; spent three hours relating my entire health history to the lead clinician in the study (Brian Walitt); and on and on. I stayed as an inpatient for two weeks, with a weekend off.
Patient recruitment was slow; the aim was 40 patients in the first phase, which would be winnowed down to 20 for a second visit to NIH a year after the first. I’m not sure why recruitment was so slow. There was skepticism in the patient community due to NIH’s longtime neglect and dismissal of the illness.
Patient advocates implored Nath to speed up the study by, for instance, bringing in two patients simultaneously. Or to bring in a patient and a healthy volunteer together. They tried this but decided they didn’t have the staff bandwidth to do it. Nath and Walitt both had many other responsibilities & studies to attend to. As a senior NIH official told me about this whole thing: Everyone at NIH has a full plate. They have to push some stuff to the side to make room for new things.
The study was unique in that after the extensive work-up in visit 1, five outside ME/CFS expert clinicians reviewed each case to decide if the patient fit all the published criteria for ME/CFS. This was quality control, to ensure patients really had ME/CFS. Three patients of the initial group were found to have other diagnoses – one had Parkinsonism, one had a rare (and fatal cancer), and so they were excluded from the second phase of the study.
In March of 2018, I returned to Bethesda for the second visit, having been unanimously judged to, in fact, be suffering from ME/CFS. During this visit – another 10 days inpatient – I took a cardio-pulmonary exercise test, which produces very abnormal results in ME/CFS. Exertion makes us sicker, and this test shows that objectively.
I also spent 4 nights inside a sealed metabolic chamber. Every calorie in and out is measured (I’ll spare you the scatological details). The chamber measures how much CO2 a person exhales, and these numbers together can measure metabolic rate. The chamber was loud – lots of fans – and I didn’t get much sleep. Here’s my arm sticking out of the chamber for blood work, with my friend Andreas filming for German television.
Visit two was exhausting. I talked with other patients in the study who were sicker than I was, and they were absolutely annihilated by it. Some took months to recover back to their already-shitty baseline functioning. It was an ordeal, but we were all motivated to help move research forward.
From early 2017 through early 2020, the under-resourced team managed to bring in something like 18 patients for two visits, and I think they hit their target on healthy volunteers. Like we all told them, it was way too slow. But it was moving forward.
Then the #covid19pandemic hit and the clinical center closed down. The team was unable to complete full study enrollment, a few patients short. Avi Nath turned his attention to autopsy studies of early covid victims to look for signs of brain damage and viral infiltration. In early 2021, the NIH team also brought in about 10 people who developed ME/CFS-like symptoms after covid vaccination, treating some with immunoglobulin & steroids.
The ME/CFS study was very much back-burnered. The pandemic was taking everyone’s attention. I talked to Brian Walitt later and asked him why the team didn’t spend the time when the Clinical Center was mostly closed to analyze the very voluminous data. I didn’t get much of a satisfactory answer, but as Nath was the PI, he was diverted to covid, and that probably is the answer.
Eventually, the NIH team formed 5 data analysis groups for the study. One for immunology, another for physiology, etc. There is so much data in this study of a small group of patients. I think the study was very ambitious, and the team was under-resourced. While 30 or so researchers were involved, most were just pitching in on very specific sub-studies. It was up to Avi and Brian to try to synthesize everything.
And finally, a few days ago – six years to the week I first entered the study – I got word that the NIH, after an extensive internal review, has FINALLY submitted their main paper from the study to a journal for publication. I suspect Avi submitted to the New England Journal of Medicine, his go-to journal, but I don’t know for sure. It took entirely too long.
And I have no idea what they’ve found, or how valuable it will be. They threw so many technologies at this illness that they must’ve found something interesting. They used a technology to look at thousands of proteins in spinal fluid, for instance. In the meantime, millions more people have developed ME/CFS after covid – an outcome obvious to all of us who have been suffering post-infectious ME/CFS pre-pandemic.
So, I don’t really know the lesson here. Yes, this is an important study, where NIH threw 30-40 different techniques and tests at a disease of unknown pathology to try to understand it. But it was seriously under-resourced for such an ambitious remit. Patients continue to suffer. We’re no closer to an effective treatment now, millions of new patients have joined our ranks due to the pandemic, and keeping a flickering flame of hope alive is challenging.
This old, 20th-century model of submitting to ‘top’ journals, waiting for peer review, then for publication, etc., does not serve patients well. It’s too slow. The pandemic showed us clinical science CAN move much faster, with preprints, online group peer-review, etc. But NIH researchers don’t have a lot of incentive to speed things along. They have good jobs for life, basically & while the team was very compassionate, they also were not in a particular hurry.
So now we patients wait again, for some journal editor somewhere to read this very large paper with tons of data in it, find peer reviewers, and then shepherd it along into publication. It could take another 6-12 months for the paper to be published. There are faster, better ways to do medical research, and I hope the field evolves to take advantage of them.
#LongCovid is, in many cases, ME/CFS. In May 2020, @Bether and I warned that this would happen in the pages of the Washington Post. The article “Researchers warn covid-19 could cause debilitating long-term illness in some patients” was extremely well-read – it was on the homepage for over 24 hours, a rarity – but it also hit the same weekend the George Floyd protests started. If not for the protests, I’m quite certain we would’ve gotten good TV and radio pick-up (broadcast people look at the top articles on WaPo and NYT and follow those stories).
I lament the lost opportunity here. If the study ends up revealing key patho-biology of ME/CFS (please g*d, I hope it does), that information could have informed the studies of #LongCovid now underway. Instead, we now have to wait for a journal to accept the article & publish it.
After the initial paper is published, there will be other papers on particular aspects of ME/CFS – substudies – that other NIH researchers will publish. Some of these papers have been finished for a year, two years, maybe longer, but Avi made the researchers hold them back until his main synthesis is published. Dr. Nath:
“However, everything cannot go into a single manuscript, so there are several other manuscripts that are going to come out. Each one of them is going to take a piece of it and describe it in more detail. So a second manuscript on muscle alone is already gone out and is under review, and there will be one on the microbiome and so on. So there are going to be a whole host of manuscripts coming out as soon as the first one gets accepted for publication…
All of this was done on 17 (not 18 as I said yesterday) patients. It is BIG SCIENCE done on a small group. The amount of data generated is mind-bogglingly incomprehensible.
The NIH also pledged that after this study finished, they would:
- Develop biomarkers
- Evaluate treatments
Last year, Dr. Nath said
“It was important to convince ourselves that there really are biological problems that are reproducible and consistent and to develop expertise to study ME/CFS, because we hadn’t looked at it before. Then we will move on to treatment studies. We have a number of different candidates [drugs] we would like to try.”
“…We’re also keen on trying to see, based on these observations, if we should try to conduct some pilot clinical studies, clinical trials, here at NIH. So those things are currently in the process of discussion.”
More details here: https://www.s4me.info/threads/usa-nih-nati
So, when this study is published, the patient community needs to remind Dr. Nath, NINDS Director Walter Koroshetz, and new NIH Director Monica Bertagnolli (nominated) that their work on ME/CFS – a not uncommon illness – has just started.
The NIH held a video call for the #MEcfs & #LongCovid community. Dr. Nath confirmed that several (or many) papers are done and will be published soon after the study’s first paper is out. He also confirmed NIH is discussing treatment trials for ME/CFS. (Thanks to the folks who listened and transcribed the call).