“MAJOR ARTICLE”
Epstein-Barr virus reactivation might contribute to exercise intolerance.
It was good to see a study from a major medical university exploring exercise capacity in long COVID and appearing in a prominent medical journal. The Journal of Infectious Diseases gave it the headline “MAJOR ARTICLE”. It came out of the very busy LIINC group at the University of California San Francisco (UCSF). In other words, it’s an antidote to the horrible (and horribly uninformed) exercise trial that the RECOVER Initiative recently embarrassed itself with.
Plus, this isn’t just an exercise study – it’s an exercise-plus study that highlights one of the great advantages of the COVID-19 pandemic – the ability to use the data that was collected as people come down with COVID-19 and relate it to what’s going on now.
The Study
The “Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID” study involved 60 participants, 87% of whom were never hospitalized, who underwent a cardiopulmonary exercise test (CPET) at least a year after coming down with COVID-19.
The study suggested that things weren’t getting better over time. Seventeen months after coming down with COVID-19, only four percent fewer participants reported having symptoms than did at 6 months post-COVID (63% vs 67%). The researchers found a reduced capacity to produce energy in 49% of the long-COVID patients. (Note that it takes a two-day exercise test to fully capture the energy production problems in ME/CFS. This was a one-day exercise test.)
Chronotropic incompetence – the inability to raise the heart rate to predicted levels during exercise has been found in both long COVID and ME/CFS.
Thirty percent of long-COVID patients demonstrated chronotropic incompetence; that is, they were unable to increase their heart rate sufficiently during exercise. They also produced less “work” (watts) and had lower peak energy levels. All this indicated that they were less able to produce the energy demanded to carry out the exercise task. Interestingly, the patients with chronotropic incompetence tended to have higher baseline heart rates – as well as lower heart rate variability (HRV). The authors noted that the opposite response – increased heart rates during exercise – is a hallmark of deconditioning.
Chronotropic incompetence isn’t a benign condition. A Framingham study that followed over 300 people over 8 years, who didn’t have symptoms but demonstrated chronotropic incompetence, found an increased risk of mortality and coronary heart disease.
Chronotropic Incompetence in ME/CFS
Workwell Foundation researchers found a strong link between functionality and chronotropic incompetence (CI) in ME/CFS. The lower the functional capacity, the fewer heart beats a person with ME/CFS was able to muster during exercise. While people with ME/CFS and mild functional impairment reached 83.1% of their age-predicted HR (mild CI), those with moderate impairment reached only 75.1% of their age-predicted HR, and individuals with severe impairment were only able to reach a staggeringly low 67.6% of their age-predicted HR.
Hot off the presses, the inimitable Visser, Van Campen, and Rowe team found evidence of widespread chronotropic incompetence, not when exercising but when undergoing a tilt table test in ME/CFS.
The lack of an adequate heart rate increase was odd given the greater reduction of stroke volume seen in the ME/CFS group compared to the healthy controls. The inability to produce sufficient stroke volume (blood pumped from the heart) should have caused the heart to compensate by beating faster but the ME/CFS patients’ hearts actually beat more slowly than expected.
This increased reduction in stroke volume upon being tilted has been found several times in ME/CFS. Several things could be causing it including low preload (Systrom), low blood volume, impaired venous pooling (Systrom), blood vessel issues, and problems with oxygen extraction (Systrom).
As we saw with the long-COVID and ME/CFS studies, the more functionally impaired the person was, the greater chronotropic incompetence they displayed while being tilted. Being tilted on a tilt table is, of course, a form of exercise. With the muscle pump disengaged, the cardiovascular system needs to work harder to maintain blood flows to the brain. The Visser, Van Campen, and Rowe findings suggest that similar cardiovascular impairments are showing up whether the ME/CFS patient is being tilted or is exercising on a bicycle.
Inflammation and Exercise
Although the authors didn’t mention it, increased levels of all three factors (IL-6, TNF, and hsCRP) have been found in ME/CFS, suggesting that a similar inflammatory state might be present. Inflammation has been proposed many times to be a key driver of the exercise intolerance found in ME/CFS.
The Epstein-Barr Virus-Effect
Interestingly, antibody tests indicated EBV had reactivated in every person with chronotropic incompetence. Most of the reactivation was driven by increased early antigen IgG (81%), although 55% also demonstrated high nuclear antigen IgG.
A trend towards Epstein-Barr virus (EBV) reactivation was associated with a lower exercise capacity; i.e. people who were unable to produce normal amounts of energy tended to have EBV reactivation (p<.11). That data finding was not statistically significant, but it was on the cusp of being so.
The EBV finding may be the first time that EBV reactivation has been explicitly linked to chronotropic incompetence or exercise intolerance. The authors did not attempt to explain how EBV reactivation might be affecting the heart, but the finding opens an intriguing avenue of exploration. If EBV plays a significant role in ME/CFS, it will probably have to affect the ability to exercise. The question is how.
The Gist
- This long COVID exercise study comes out of the busy LIINC long COVID research group at the University of California at San Francisco. The study assessed the exercise capacity of long COVID and recovered COVID patients a year or so after they were infected.
- Plus, since the researchers had prior data on immune factors and Epstein-Barr virus reactivation they were able to patch those into the analysis.
- Almost a year later the long haulers were sticking around. Sixty-three percent still had symptoms compared to 67% with symptoms 6 months after becoming infected; i.e. almost a year later only 4% of patients no longer had symptoms.
- The exercise findings were similar to what we’ve seen in ME/CFS – reduced exercise capacity in about 50% of the long COVID patients compared to the healthy controls. (Note that it takes a 2-day exercise test to fully assess exercise capacity in ME/CFS).
- Plus chronotropic incompetence – an inability to raise heart rates to the expected levels during exercise – was found in about 30% of the long COVID patients. People with more symptoms tended to exhibit more chronotropic incompetence.
- Similar findings have shown up in several ME/CFS studies. One study that went further than the others strongly linked chronotropic incompetence (CI) to functionality. The more severe the patient was the more CI was found. In fact, the most functionally impaired ME/CFS patients were able to produce only about 2/3rds of their expected heart rate increase.
- Hot off the presses the inimitable Visser, Van Campen, and Rowe team found evidence of widespread chronotropic incompetence not when exercising but when undergoing a tilt table test in ME/CFS.
- The lack of an adequate heart rate increase was odd given the greater reduction of stroke volume seen in the ME/CFS group. The inability to produce sufficient stroke volume (blood pumped from the heart) should have caused the heart to compensate by beating faster but the ME/CFS patient’s hearts actually beat more slowly than expected.
- As we saw with the long COVID and ME/CFS studies the more functionally impaired the person was the greater chronotropic incompetence they displayed while being tilted.
- Interestingly, antibody tests indicated EBV had reactivated in every person with chronotropic incompetence. A trend towards Epstein-Barr virus (EBV) reactivation was also associated with a lower exercise capacity; i.e. people who were unable to produce normal amounts of energy tended to have EBV reactivation (p<.11).
- This may be the first time EBV reactivation has been explicitly linked to chronotropic incompetence or exercise intolerance.
- The authors had ample opportunities to link core findings in ME/CFS to long COVID (reduced exercise capacity, chronotropic incompetence, invasive exercise, problems with peripheral blood extraction, elevated sympathetic nervous system activation, low HRV, preload failure, orthostatic intolerance, small fiber neuropathy, disordered breathing patterns) but, unfortunately, chose to ignore them.
- Still, the similar findings in this study and others link long COVID more strongly to ME/CFS and open up the intriguing possibility that EBV reactivation is associated with exercise intolerance.
The “Ignoring Chronic Fatigue Syndrome (ME/CFS)-Effect”
The authors also noted that problems with “peripheral oxygen extraction” (i.e. problems with getting blood to the muscles, or the mitochondria taking up oxygen from the blood) could be responsible. That hypothesis – and the data to support it – has engaged ME/CFS researchers for about 5 years now.
You wouldn’t know that from this article because the authors almost totally ignored ME/CFS – thus producing a different effect which includes exclamations, increased heart rates (no chronotropic incompetence there), clenched jaw, etc. How ironic it was that a group called LIINC almost completely ignored the many linkages between the data they produced and long COVID’s sister illness, ME/CFS.
They did mention early findings of elevated IgG EBV in ME/CFS, and stated that given the post-exertional malaise found in ME/CFS, care with exercise – which they recommended for chronotropic incompetence in long COVID – be given.
They ignored, though, multiple opportunities (reduced exercise capacity, chronotropic incompetence, invasive exercise, problems with peripheral blood extraction, elevated sympathetic nervous system activation, low HRV, preload failure, orthostatic intolerance, small fiber neuropathy, disordered breathing patterns) to link core problems in ME/CFS to long COVID.
It’s always surprising when research groups interested in long COVID ignore relevant findings in ME/CFS that one would think prop up their results, and in doing so, ignore the original long haulers who continue to struggle for funding and validation.
Whether the folks at LIINC give a darn about ME/CFS, the crucial thing is that the findings between the two diseases (reduced exercise capacity, chronotropic incompetence, low HRV, preload failure, etc.) continue to match up, and anyone who cares to look will see that.
Excellent article! Thank you!
You’re welcome! 🙂
Excellent Cort. Can’t thank you enough
Thanks!
I do think they really try to keep the conditions separated. Mainly, or I hope so, out of research considerations. You can’t mix conditions until you really know they’re the same. For one, noone would finance that.
As I read more about long covid the more ME shows up in the discussions, ME and the same technologies, findings etc, so if – or when – results appear then they also can be applied on ME to evaluate if it is the same things going on.
I do not care if ME researchers was first in finding clues, it might be faster if long covid researcher had listened on ME dito, but as long as progress is made I don’t care really. The many roads, Rome and all that!
I am trying to look through things and concentrate on the progress happening due to covid research.
My fear is that the interest from researchers decrease with time, with both (and other similar) diseases, but again it seems to me like a new area in medicin really is developing as more advanced tech and measurements are popping up. I hope.
And thank you, ofcourse! Much!
Thanks for taking such a balanced approach. All your articles are sufficiently detailed and scientific whilst also being easy to understand. Nice work.
Thanks!
Well said.
Thank you CORT for another amazing article. Although I have had this disease for 40 years and it is progressing in symptomology, I still have hope.
These results on ABV are amazing. Although I have not tested positive for the active form of the virus, I have always had high titers of the others.
Let us hope that researchers are not only able to tie in EBV to the disease, but find a way to treat this elusive virus.
Thanks for another great piece!
Coincidentally, I had an EBV panel a few weeks ago and it was positive for early antigen IgG. This happens chronically – a chronic acute reactivation!
(High nuclear antigen IgG at the same time. We retested a week later and had the same result.)
I don’t quite know how to think about it.
I’ve suffered from this for years, and yes, I’m always positive for ebv igg and igm. My neurologist said it’s definitely a post viral issue, however I never had covid, but some strange lung virus two years prior. The biggest help for me is coq10 ( can’t miss a day) and a lot of water. It’s affected every system of my body.
They look ignorant – whether they are or not. And they could have SO easily just indicated they were sticking to one cohort. If they didn’t want to ‘contaminate’ their results with a mystery disease of long standing.
This is always discouraging for those of us who have not benefited from OUR tax money being spent on our disease.
Petty of them.
Sorry, Cort, but p < 0.11 is not on the cusp of anything. Significance in medical research is p < 0.05 and anything larger than that is simply not significant. No cigar. It's like being pregnant; either you is or you ain't. p < 0.11 means that the probability that this result happened by chance is too high to be able to claim anything.
This is not true. A statistical trend (p < 0.2) can point to relevant associations or differences if your power is limited (e.g. because of too few subjects).
Say, a study with 50 subjects and controls may give you a trend only for a certain measurement, which then may turn out to be significant in a study of 500 subjects. So researchers do have an eye on statistical trends too but they know how to interpret them.
Maybe my words “on the cusp” were too strong but the authors did highlight this result. If it was meaningless I don’t think they would have done that. They didn’t claim they found an association – it was more something to note.
P<.11 means there is an 11 percent of the result being due to chance. P <.05 means there is a 5% chance of that happening. The 5% rule "rules" but it was a somewhat arbitrary rule developed in the 1920's "It is generally understood that the conventional use of the 5% level as the maximum acceptable probability for determining statistical significance was established, somewhat arbitrarily, by Sir Ronald Fisher when he developed his procedures for the analysis of variance." The question is how much risk is one willing to take? Yes, an 95% probability that an result is not due to chance is better than an 89% probability that a result is not due to chance but you still have an almost 90% probability that the result was correct. That's worth noting - a few more people on one side or the other - and it might have been a "significant" result.
Of course it’s true that if you add a few people to one side or the other you get a different result. Especially if you get to choose those people! And of course it’s true that a small sample size limits your power and what you can claim based on those results. And of course it’s true that a “p” value that is not significant can indicate a trend. But it does not mean that you can claim that your hypothesis is supported when you have p < 0.11. It means that there is an 11% probability that this result happened by chance. By convention, that's not enough. It means that there is an 89% probability that it did not happen by chance, i.e. that something is going on here. You are not allowed to say that you know what that something is. It just means that there has to be a lot more statistically significant evidence published before we can say that we might now know what that something is. It might be how they tie their shoes! It might be some artifact of testing or something else. In the pyramid of evidence, studies without statistical significance rank very low. Meta-analysis has a big problem with including studies such as this:
https://pubmed.ncbi.nlm.nih.gov/30514161/
"meta-analysts should not exclude these studies because their exclusion would bias the meta-analytic outcome, but also they cannot be included as null effect sizes because this strategy is also associated to bias."
I don't want to argue the arcane issues of statistical inference. I'm just really tired of studies that trumpet results that are not statistically significant. A trend! Yay! Good for you, now get back out there and do something that has statistical significance, is replicable, and is generalizable to your subject population.
I try [almost] everything that has helped someone, somewhere, some time, research or no. If it helps, I keep it. If it doesn't help, I give it up. But these people who do research are trying to build general knowledge. Do it right. I excoriated my own dissertation committee member for doing this very thing. "But it's so close!' she said. "But it's not significant!" I answered. "Besides, you did it post hoc." She revised her conclusions and got it published. But this was a very long time ago. Maybe sloppy write ups are ok now.
I'm done with my rant. I'll shut up now.
I had covid, then long covid since aug 2022 and still dealing with it. Very extreme fatigue. My ebv scoring is way over 750 and has been for months. Wish there was more help with all these symptoms.
Let’s hope it’s coming…Finally some attention is being paid to post-infectious illnesses.
Sorry to hear you’re dealing with long-covid… still. ☼Are you receiving ANY treatment for your long covid / EBV reactivation ..??..
I had chronotopic incompetence during CPET.
Why would my heart pump faster if there isn’t enough to pump up anyway.
I’m pretty sure it is a huge indication of lowered blood volume.
When two patients with the same total body mass have different blood volumes, one has 4 liters and the other has 5 liters can you really compare them in lab tests? Lowered blood volume has existed for years(decades) and all components in the blood must have adapted to the lowered blood volume.
When I do a CPET my body comes up short, just 40%VO2 max; that’s when lowered blood volume(and venous pooling) make a difference.
When a liter or more blood is missing, I can’t use what should have been in that missing liter.
Isn’t it true that you can also have chronotropic incompetence with POTS?
https://pubmed.ncbi.nlm.nih.gov/36818521/
Compensation?
Just reading the detail on EBV enlightens me a little on something that was mentioned to me recently on a private Dr consultation because I have struggled with information from my GP practice.
I’ve suffered with CFS/ME since 2010 which started around a month after shingles. I have since had an annual bout of shingles every year since, until recently when I have now had 4 bouts since June last year and current shingles symptoms. I have all the symptoms in the 3rd paragraph up above.
Can anyone help with more information on this or any help I can find?
Hi Cort,
This is a great summary of our article, and I really appreciate your take on it including the criticisms that we did not adequately emphasize the overlap with exercise physiology in ME/CFS. As you pointed out, we did not do 2 day CPET or iCPET in this study. We are keenly aware of the overlap between our findings and those in ME/CFS (see Todd Davenport’s work or David Systrom’s work), even more so now than when we first designed this study 2 years ago thanks to amazing patient advocates. Wish there was more space for us to have expounded on the connections (as we did in earlier drafts) but had to cut a lot with JID’s word and reference limits. We originally were not looking for the EBV connection, but were encouraged by the JID reviewers/editors to do so and to our surprise everyone with chronotropic incompetence had evidence of EBV reactivation. We’re really fortunate they made that suggestion–but it also made us scramble to trim our paper down to the word limit and unfortunately I think we cut too much in the discussion about ME/CFS.
Humbly,
Matt Durstenfeld
That’s so good of you to take the time to reach out and explain, Matt. It is much appreciated! And thank you so much for your focus on long COVID. We in the ME/CFS community are very excited about your work. 🙂