Reprinted with the kind permission of Cort Johnson and HealthRising.org.
The coronavirus presents both a curse and a potential blessing. The curse is obvious – millions sick, many dead, economies under siege, etc. The blessing is less obvious, but for people with chronic fatigue syndrome (ME/CFS) and other post-infectious diseases, such as autoimmune diseases, it’s clear. Researchers have been given the gift of a huge laboratory, really, in which to understand how a simple infection can lead to chronic diseases long after the infection has been vanquished.
We’re facing an unprecedented situation – a worldwide pandemic that’s caused – in what’s surely a huge undercount – 63 million documented infections and 1 1/2 million deaths. While the vast majority of those infected with the coronavirus will recover and go on with their lives, some will suffer its after effects, such as lung, kidney or neurological damage. Others may come down with autoimmune diseases. Anthony Fauci, the director of the big immune institute at the NIH, has reportedly said that he believes from 10-30% of those sickened by the virus may have problems recovering.
As Ian Lipkin noted early on, it’s going to take years to fully assess the impact of the SARS-CoV-2 coronavirus. If studies in the past, which suggest that from 5-10% of those people sick enough to see a doctor because of an infection come down with ME/CFS, though, possible that millions of people may come down with ME/CFS.
The huge question facing the both the long haulers and the ME/CFS community is whether the research community at large will use the laboratory, or opportunity that’s been presented to them, to understand how post-infectious illnesses occur. Unfortunately, post-infectious illnesses have been amongst the least studied in all of medicine. That means that outside some ME/CFS researchers, there’s been no cadre of post-infectious researchers waiting in the wings to pounce on the coronavirus when it came.
ME/CFS Community Gets to Work
Recognizing the opportunity before it, the ME/CFS Community sprang into action. The Solve ME/CFS Initiative devoted its Lobby Day to educating Congressmen and women about the COVID-19 ME/CFS connection, and then used the COVID-19 connection to strike at a long-sought prize – direct Congressionally mandated funding, and oversight of ME/CFS research at the NIH. While that effort has not made it over the finish line yet, it’s resulted in a remarkable 52 Congressmen signing on.
The Solve ME Initiative has also partnered on COVID-19 / ME/CFS research grants, supported major media articles, created a long-hauler webinar, reached into the long-hauler community, and will soon be tracking the long haulers in its Patient Registry.
For its part, MEAction reached out to the long-hauler community, produced webinars, and launched the “Stop.Rest.Pace.” campaign to help educate long haulers and medical professionals. It has helped to place long-hauler / ME/CFS stories in major media outlets including the The Washington Post, CNN, The Atlantic, Time, and The Guardian.
Plus, in “Rehabilitating COVID-19 “Long-Haulers”: The ME/CFS Connection” Workwell used their two-part accredited MedBridge course on ME/CFS to support health care personnel in understanding and managing the long haulers they are seeing.
The rubber really meets the road, though, at the same old place – funding. We don’t really get anywhere until the long haulers are prodded, scanned, and sampled enough to tell how a coronavirus infection turns into diseases like ME/CFS.
Pitiful NIH Response
The coronavirus has put the strengths and weaknesses of our national institutions in stark relief. Claudia Carrera of MEAction came in at the very end of the recent interagency NIH discussion to deliver a splash of hot water.
Carrera asserted that the long-hauler train that appears to barreling down the tracks at our medical system warrants “a massive coordinated response to take place across agencies at warp speed. In short, the NIH should engage in a “top down strategic effort, driven by task forces and offices with real authority”. Dr. Koroshetz, who can be refreshingly honest at times, agreed with everything she said.
The pitiful answer, though, was that there was no plan or strategic effort. The NIH is going about the long-hauler issue in the same way it usually does: letting things would unfold as they unfold. The long haulers, like the ME/CFS patients before them, were going to be left at the mercy of the medical research system.
Francis Collins’s Sept. 3rd blog, “Citizen Scientists Take on the Challenge of Long-Haul COVID-19”, which managed to be both encouraging and infuriating at the same time, was a case in point. Lauding the “citizen scientists” at the Body Politic who created the first large-scale post-COVID survey, Collins thankfully highlighted the fact that even mild cases of COVID-19 can cause significant long-term health effects. Yet Collins, who always finds a way to laud the NIH for something in his blogs, was unable to point to a single program the NIH had created to help the long haulers.
That doesn’t mean nothing is being done – there’s simply no coordinated effort underway.
The First Need: Long-Term Observational Studies
“You need a lot of patients to study anything. We will have enough patients to study at least that kind of ME/CFS that develops following COVID.” Anthony Komaroff
I looked through approximately 120 studies that popped up when using the search terms “sequelae” and “COVID-19” on the clinicaltrials.gov and projectreporter websites to try to figure out what kinds of studies feature the long haulers.
Two separate issues need to be addressed. First, simply documenting the presence of long-term fatigue and other problems is crucial. It may, in fact, be the most important task – as the documenting of large numbers of still sick people should unlock more funding down the road.
On this issue, the news was very good. Enough tracking studies appear to be underway that if an ME/CFS cohort (or other cohorts e.g. fibromyalgia, neurological diseases, lung problems) show up, it should be found.
All of the studies below are following coronavirus patients for at least one year. The one that requires hospitalization will include less severe hospitalized patients.
- Nancy Klimas will be following 2,200 COVID-19 patients over time South Florida in a $4 million study.
- Avindra Nath is following 1,200 COVID-19 patients over time.
- Leonard Jason is tracking several hundred COVID-19 college students over time.
- A 900-person study assessing COVID-19 outcomes is slated to last through 2027.
- A 150-person observational COVID-19 Norwegian study runs through 2023.
- A 250-person Columbia study tracks COVID-19 patients over one year.
- A 250-person Johns Hopkins study will compare inflammatory/immunological, physical, pulmonary, and neuropsychological status in severely ill patients vs patients who simply received oxygen during hospitalization over 12 months.
- A 400-person French study will study sleep, exercise capacity and respiration in COVID-19 patients for five years.
- A huge (4,000-person) European study will follow anyone with respiratory issues (such as cough, sore throat, etc.) after an infectious illness for two years.
- A 350-person New York University study will assess COVID-19 outcomes over several years in its survivorship database of coronavirus patients.
- A year-long Australian study at St. Vincent’s Hospital in Sydney is following 100 COVID-19 patients.
I’m surely missing some studies but it’s clear that if an ME/CFS-like post COVID-19 cohort shows up, we will know about it. If its large enough, it will set the long haulers – and hopefully people with ME/CFS – up for studies for years to come.
The Understanding Long-Hauler Studies
Studies that dig deeper will hopefully ferret out the clues we need to understand post-COVID 19 and ME/CFS.
The Hospitalized Patients Situation
“One challenge is differentiating post-viral fatigue syndrome and ME/CFS from the lingering effects of being in an intensive care unit or on a ventilator, which are known risk factors for long-term ill health.” Joseph Breen, NIAID – Washington Post
Hospitalized patients present some positives and some negatives. The ideal cohort for an ME/CFS study would seem to be one that matches the majority of ME/CFS patients at the time they became ill – mostly healthy, younger, or at least not old, people, who came down with a cold they were never able to shake. Because the infections that trigger ME/CFS rarely land people in the hospital, COVID-19 patients who are hospitalized present at least a somewhat different cohort.
One danger with focusing on hospitalized patients could conceivably someone making the argument that it makes sense for someone who was hospitalized to remain ill – they, after all, had a serious infection. Everyone else, on the other hand, just had a cold. Why are they still ill?
There are benefits (see below) to using hospitalized patients as well. Ultimately, it’s best that both non-hospitalized and hospitalized patients and that’s what’s occurring.
Hospitalized patients can be differentiated into two types: ICU and non-ICU patients.
Patients who have been in intensive care are problematic since they receive treatments and undergo procedures such as sedation, immobilization, drugs and ventilation that produce their own costs.
Simply being in a critical care unit is known to produce long-term effects, some of which mimic ME/CFS. Post-intensive care syndrome or chronic critical illness are two terms that have been used to characterize long term problems with recovery after being in the ICU.
Long lasting fatigue, in particular, is extremely common with one study reporting that 50% of ICU patients experienced severe fatigue six month later. A recent paper stated that, with regard to COVID-19 patients in the ICU:
“Prior studies of patient survivorship after an intensive care unit (ICU) stay suggest that many critically ill patients with COVID-19 will face long-lasting physical, cognitive and/or mental health impairments.”
The paper noted that COVID-19 patients with severe respiratory failure may require long periods of “mechanical ventilation, deep sedation, neuromuscular blockade and the associated immobility which increase the risk of physical impairments.”
Prolonged ventilation can cause diaphragm dysfunction and other injuries. Plus, COVID-19 patients in the ICU may have receive drugs like hydroxychloroquine, steroids, antivirals, anticoagulants, etc. that few people with ME/CFS receive. People in the ICU also often experience “prolonged delirium“.
The fact that the fatigue was correlated with male gender, a diagnosis of major depression, and a prior history of anxiety disorder in these patients also suggested that many of them may be different from ME/CFS patients.
References to post-traumatic stress disorder are also rife in post-ICU syndrome and cognitive behavioral therapy is frequently recommended. One overview reported that from one quarter to one-third experience “anxiety, depression and post-traumatic stress disorder (PTSD)“.
So many things are going on in COVID-19 ICU patients that it’s difficult to say what’s causing what. Even if they end up meeting the criteria for ME/CFS, the presence of other disease classifications like post-ICU syndrome would make it hard to classify them as ME/CFS patients.
Hospitalized COVID-19 Patients
Simply being hospitalized for COVID-19 results in a different kind of patient being assessed, as well. One study found that risk factors for hospitalization due to COVID-19 included severe obesity, diabetes, chronic kidney disease, hypertension and asthma, as well as being older, and being male.
Several studies have found that nearly all hospitalized COVID-19 patients had more than one underlying condition, with hypertension, obesity and diabetes leading the list. Thirty percent had some sort of lung disease, 34% had coronary artery disease or congestive heart failure, and 22% had a neurologic disease.
While younger COVID-19 patients can be hospitalized (12% were between 18-40 years old), most are older (65%>50 years old; 45%>65 years old). Almost half were diagnosed with pneumonia, 40% experienced acute respiratory failure, 18% acute kidney failure, 18% sepsis and 10% acute respiratory distress syndrome (ARDS).
Hospitalized patients then present a different slice of post-infectious illness than we typically see in ME/CFS.
On the other hand, most COVID-19 patients who end up being hospitalized do not end up in the ICU or on ventilation. (One large study found that 32% required ICU admission and 19% ended up on ventilation.) The majority of hospitalized COVID-19 patients who probably simply receive oxygen and do not experience any kind of lung or organ damage wouldn’t seem to present a problem.
There are also some pros to using hospitalized patients. They’re a lot easier to find, and will have the results of numerous blood and other tests. Plus the fact that they are severely ill suggests they’re probably more likely to come down with an ME/CFS-like illness; i.e. you may be able to get more bang for your research buck using hospitalized patients.
Plus, you could compare them to post-ICU patients and see if similarities emerge. Dominic, after all showed us how similar post-ICU may be to people with ME/CFS. If similarities did emerge, a new and bigger world of ME/CFS could potentially open up. ME/CFS may not be simply the result of “ordinary infections”; it also shows up in critically ill patients. Post-ICU syndrome could be ME/CFS. An outcome like that could broaden the disease and increase its impact. In the end, it’s important that some hospitalized patients be assessed.
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Once researchers started looking for fibromyalgia in other pain diseases, it showed up in spades. A portion of the patients in every chronic pain condition – from arthritis to multiple sclerosis to lupus to migraine – come down with fibromyalgia.
Could having a serious illness do the same for ME/CFS?
The NIH Studies
Unfortunately, the NIH is taking a laissez-faire approach to the long haulers. There’s no rhyme or reason to the studies it’s funded. It’s simply responding to researchers who have chosen to apply for grants.
That tells us some things about the NIH. One is that media attention only goes so far. Long-hauler stories have permeated biggest media outlets. Virtually everyone knows what “long hauling” is now, yet the NIH has not responded with any initiatives. It appears that either it takes a major political crisis (the opioid epidemic) or Congressional action (the Shark Tank) to get the NIH out of its rut.
When the NIH has moved with ME/CFS, it did so after internal NIH initiatives such as the IOM Report (research centers) or the NANDSC report (strategic report) were produced.
The consequence of the NIH taking a hands-off approach to the long haulers is a mish-mash of studies that range from assessing COVID-19’s long-term effects in people with Alzheimer’s, or high-risk expectant mothers, in people in Haiti, or people at risk for HIV.
Ideally, we want a comprehensive. broad-based study focused on long haulers who mimic people with ME/CFS; i.e. mostly healthy, mostly younger people. The one notable non-ME/CFS long hauler study that I could find – a UCSF long-term, longitudinal study – focuses on immune factors. Thankfully, it will include a wide spectrum of SARS-CoV-2 infection severity, and collect large volumes of peripheral blood and saliva during frequent intervals over two years. This study could tell us much – yet even it is too limited. We need studies that assess the many other factors that may come into play for ME/CFS.
The long haulers should note that all of those feature ME/CFS researchers.
The ME/CFS-Focused COVID-19 Studies
Four Steps Ahead of the Game – The Nath Study
Who knew back in 2015 that Avindra Nath would turn out to be such an potentially seminal figure? Now it’s Nath who’s leading the charge on the long haulers at the NIH. Nath has been all over the media, calling for more and more research on the long-term effects of COVID-19. Nath is making it clear that having established researchers in the NIH wheelhouse is incredibly important.
When COVID-19 came, he was ready. In the interagency NIH call, Nath said his team was “four steps ahead of the game”. They already had a protocol, they had a team of investigators standing by, and they understand aspects of it.” They, he said, “are in a very good place …”
He was clearly excited at being able to catch the disease in the act. The long haulers are different, after all, from his ME/CFS patients who’d become sick within two years. The long haulers are freshly ill. Their systems are evolving right now. Only Lenny Jason, with his samples from his pre-mono healthy students, has a possibility of getting a closer look at ME/CFS in its inception.
Beth Mazur of MEAction was on top of the announcement when it came. As soon as the 1,200-person Avindra Nath study was up, she was on it, tweeting about it.
In September, Brian Walitt reported they’d already received 1,000 calls from COVID-19 patients. The 1,200-person study will follow long haulers over time, and identify some individuals who will participate in Phase III of the study: an “ME/CFS / COVID-19 deep phenotyping approach”; i.e. Nath is going to will throw the kitchen sink at them. In fact, the study overview specifically refers to the approach Nath took with ME/CFS:
“The deep phenotyping methods employed will be synchronized with other NIH-approved deep phenotyping protocols to foster cross-phenotype comparison research with other medical syndromes, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness. Deep phenotyping characterizations would be used to generate scientific hypotheses for testing in future studies.”
The NIH is doing the same intense, deep dive into Gulf War Illness that it’s been doing in ME/CFS. The peak exercise tests, the brain functioning, the immune, autonomic, metabolic, mitochondria, microbiome, gene expression studies – they’re all in there.
So – Nath’s ME/CFS intramural study has spawned a COVID-10 long hauler and a Gulf War Illness (GWI) study. what is the only reasonable conclusion we can draw from that? That Nath’s MECFS study has been successful; i.e. Nath has found enough from his ME/CFS study to warrant doing the same kind of very intensive study in COVID-19 and GWI. That’s very good news for us.
That’s not it for Nath at all, though, who appears to be a very busy man. Nath is also doing a separate 50-person study of the neurologic problems following COVID-19 that includes brain scans, lumbar punctures, and cognitive testing. Nath, who believes that inflammation is probably at play in the long haulers, has already performed autopsies on almost two dozen COVID-19 patients.
Plus, back in 2015, Nath started a 1,000-person study to learn how inflammation and infections affect the brain and nervous system. The study is open to people with known or suspected infection or inflammation of the nervous system; i.e. people with fever, signs of infection in the cerebral spinal fluid or MRI, or a clinical history of infection.
Many people with ME/CFS would probably fit fine in this study. As with the other studies, Nath will follow the participants over time, taking blood, urine, and saliva collection; doing neuroimaging and a spinal tap and possibly other tests. The study runs through 2025.
We were very lucky to get Nath.
The $4 Million Dollar Study – Nancy Klimas Takes on the Long Haulers
Four million dollars – for one of our top researchers – to study the long-term effects of COVID-19 … Now, that’s a study.
It wasn’t the NIH which funded it – it was the CDC – which is well acquainted with Dr. Klimas’s ME/CFS work, . which surely helped Dr. Klimas get this $4 million dollar-plus grant.
The big study will follow 2,200 people from a diverse array of backgrounds in Southern Florida, 200 of which will get more extensive workups at the clinic. Unfortunately, that’s all I know.
Getting at the Molecular Basis of Long Hauling (and ME/CFS) – The OMF Study
The OMF has received $1,000,000 to dig deep into the molecular underpinnings of formerly hospitalized COVID-19-triggered ME/CFS patients. The study, which involves all four of the OMF’s research centers, will undertake detailed genomic, metabolic, and proteomic analysis over time.
This is exactly the kind of broad, comprehensive analysis that we’re not seeing in non-ME/CFS-oriented studies. It’s the kind of study that could probably only come from ME/CFS researchers. It’ll be fascinating to see what Tompkins, with his background in sepsis, finds out.
The Linchpin – Leonard Jason’s Unique Opportunity
Leonard Jason quickly applied for and got a university grant to assess the effects of COVID-19 in the almost 5,000 college students he’d already been tracking after they came down with infectious mononucleosis. He reported that about 5% of the college students he’s contacted have come down with COVID-19.
Jason, then, is in the unique position of being able to compare two post-infectious cohorts to study at the same time. Jason could ultimately tell us if the coronavirus and EBV trigger ME/CFS in different ways.
Plus, because he’s the only one who has blood samples from before the participants became ill – Jason’s study provides the scintillating possibility of identifying an immune hole that let the whole process get started in the first place.
Jason’s already found a possible immune hole (reductions in IL-5, IL-6, IL-13) in the college students who came down with ME/CFS after a bout of infectious mononucleosis/glandular fever. Next, he will look for one in the college students who come down with ME/CFS after COVID-19. Jason will also look to see if the immune networking gets altered in both cohorts after they became ill.
Like Nath, Jason was set up to tackle COVID-19 when it showed up. His prior infectious mononucleosis study was able to fold perfectly into a COVID-19 study when the coronavirus showed up. Examining the effects of COVID-19 and infectious mononucleosis in a perfect cohort of young and healthy patients provides a precious opportunity to catch ME/CFS in its tracks. The only question in my mind – does Jason have the money he needs to fully investigate these patients?
There is hope! It’s clear that the rate of ME/CFS that shows up in the long-hauler community is going to be documented. If all goes as expected, that should set the long haulers up for studies for years to come.
The most optimal time for studying is now, though – as the long haulers are getting ill. The pandemic is certainly cooperating. While it’s unfortunate for those afflicted, the new heights the pandemic is roaring to are providing researchers a distinct – but also limited – window of opportunity.
The good news is that we have four excellent studies that are ploughing ahead trying to understand what’s happening as COVID-19 patients convert to ME/CFS.
The bad news is that we have four studies – not the dozens the long hauler situation warrants or the ME/CFS community deserves. That’s partly a consequence of the NIH yet again taking a hands off approach.
Some long haulers have winced at being associated with ME/CFS and there has been talk of creating a new disease for them. They should know, though, that what was predicted – that the NIH would not rally to their cause – and that the research community would not spring to study them – has occurred.
Most COVID-19 sequelae studies are limited in focus and are focused on the severely ill. Very few in-depth studies are focused on the formerly healthy people that make up the vast majority of the long haulers, and those that are have come mostly out of the ME/CFS research community. Those studies are more comprehensive and are using insights gained from past studies to inform them. Without them the long hauler community would be in real trouble.
In other words, the long haulers who fit the criteria for ME/CFS would be best served by sticking with us and fighting with us for more funding.
The few studies we have are certainly promising. Nath’s study is doubly intriguing because he will apply the insights he’s learned (whatever they are!) from his ME/CFS study to his COVID-19 and GWI studies. Should those findings hold up, we could conceivably have validation across three different entities – something that would one would think, be a game-changer. The fact that this is coming from Nath, the well-respected head of the NINDS effort at the NIH’s big hospital, means his results will get heard.
We don’t know much about Nancy Klimas’s study except that it’s big and expensive – and is in the hands of a creative and respected researcher. Good for the CDC for giving her what must be one of the more expensive studies they’ve funded.
The Open Medicine Foundation’s study will undoubtedly use the insights it’s gathered from the severe ME/CFS study to inform its work, as well. This study will dig the mostly deeply of all the studies into the molecular dynamics at play – providing a nice counterpoise to Nath’s work.
Lenny Jason’s provides a unique opportunity to assess the health status of future ME/CFS before and after they become ill. Jason’s study could uncover the immune – or other – hole which allowed ME/CFS to appear once the infection took hold. It could provide the linchpin, if it all works out, that definitively explains ME/CFS.
Other studies into the coronavirus will provide their own insights into what happens during the early stages of infection and illness. Plus, other long-term studies are underway. The 20 plus grant applications ME/CFS researchers put into the Congressionally Mandated Medical Research Program (CDMRP) earlier this year could provide more help. We got into that program (thanks Solve ME) at just the right time.
It’s impossible to tell what these studies will find but it’s hard to believe that they won’t provide important insights into both the long haulers and ultimately ME/CFS.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.