Inflammation, Epstein-Barr Virus and Exercise Intolerance in Long COVID

by Cort Johnson | May 21, 2023 | Cytokines, Epstein-Barr Virus, Exercise, Homepage, Inflammation, long COVID, Pathogens | 27 comments

“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.

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