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It’s always good to see an exercise test in chronic fatigue syndrome (ME/CFS). It’s harder on the patients – kudos to them for participating in the study –  but study after study has shown that exercise allows researchers to dig deeper into what’s going on.

Dr. Montoya of Stanford was the senior author and Kegan J. Moneghetti, a Stanford physician researcher focused on cardiovascular medicine, was the lead author.  The idea – to explore what exercise did to ME/CFS patients’ immune and cardiovascular systems and metabolism – was a decidedly good one.  We need as many exercise studies as we can get.

exercise

Exercise is hard on the ME/CFS participants but usually results in better results.

The paper stated that they used a submaximal exercise regimen to explore energy production (VO2 max, etc.), and the cardiovascular and immune systems.  An echocardiograph measured left and/or ventricular mass, volume, wall thickness, pressure, stroke volume, etc.  Vascular stiffness was measured before and after exercise using ultrasound.  Fifty-one cytokine and growth factors were measured at baseline and 18 hours after exercise.

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. www.nature.com/scientificreports 2018 Kegan J. Moneghetti1,2,3, Mehdi Skhiri4, Kévin Contrepois1, Yukari Kobayashi1,2, Holden Maecker5, Mark Davis5, Michael Snyder1, Francois Haddad1,2 & Jose G. Montoya.

The Immune System and Exercise

A surprisingly large number of studies have examined immune factors after exercise in ME/CFS.  The results, unfortunately, have been surprisingly underwhelming given the role the immune system is believed to play in producing the post-exertional malaise in this disease.  On the other hand, the studies have been small and usually examined only a small number of immune factors. Lloyd’s negative 1994 study, for instance, tested only four cytokines.

A 1999 study which exercised 20 ME/CFS patients to exhaustion and found no immune differences (WBC, CD3+ CD8+ cells, CD3+ CD4+ cells, T cells, B cells, natural killer cells IFN-gamma) concluded that the “immune response” of ME/CFS patients in response to exhaustive exercise is “not significantly different” from sedentary healthy controls.  A small early study finding only modest differences likewise suggested that “cytokine dysregulation” is not a dominant factor in ME/CFS.

A larger 2003 CDC study (32 patients) which tested complement factors and cytokines at 4 time-points found alterations only in C4a.  Nijs found no such changes in either it or Il-1 beta in a 22 patient study.  Robinson found no changes in IL-6 or its receptor in his 33 patient 2010 study.  White failed to find any differences before and after exercise in nine cytokines in his 24 patient study.

Light’s 2010 study – one of the few to produce really significant results – did so only by contrasting 11 ME/CFS patients with high symptom flares (high pro-inflammatory cytokines) with 9 patients with low symptom flares (reduced pro-inflammatory cytokines) after exercise.

As with other cytokine studies, the results from exercise studies have demonstrated little consistency. The Moneghetti/Montoya 24 person cytokine study is modest in size and only examines them at two time-points (before and 18 hours after exercise) but looks at the most cytokines (51) yet.

Results

CPET

The paper did not mention which exercise protocol was used but reported that, “All participants underwent symptom limited exercise”; i.e. they experienced fatigue, dizziness, shortness of breath that caused them to stop the test.

The title of the paper stated the researchers employed a submaximal exercise test. A controversy has been brewing for quite some time over whether it’s best to use submaximal or maximal testing in ME/CFS. “Submaximal” exercise tests sound like they’re stressing patients less but submaximal tests can have ME/CFS patients exercising at a higher rate for much longer than maximal tests which tend to be briefer.

The RER results (1.14 – patients; 1.18 – healthy controls) – which are an indicator of effort – indicated that this was essentially – despite the title – a maximal exercise test. Some differences in the literature do exist. The American Heart Association and other groups state that a 1.10-1.30 and above  result indicates that a maximal effort was given. Some groups do require a 1.15 result.  Whatever the interpretation, with both groups of participants above or very near the 1.15 mark and well above the 1.10 mark, this appeared to have been a maximal exercise test.

Not surprisingly given the one-day exercise testing regimen, neither maximal heart rate, VE/VCO2, peak VO2, RHI, VE/VCO2, peak VO2 during recovery or 18 hours later were significantly different between patients and healthy controls.

Fatigue scores were not correlated with peak VO2 in this study; i.e. the patients reporting more fatigue did not have lower peak VO2 values. Citing their exercise findings and a heart failure study, the authors warned against associating the degree of fatigue found in ME/CFS with exercise impairments. The heart failure study found only modest correlations between the response to an exercise test and symptoms.

The fact that no difference was detected between CPET parameters between both groups despite marked difference in MFI-20 scores highlights the difference between reported symptoms such as fatigue or dyspnea and exercise performance measured by peak VO2. This underscores the importance of not using these two concepts interchangeably.

That statement opens a can of worms. It’s true that researchers have been unable to correlate multi-functional index (MFI) scores with VO2 max scores (or the peak VO2 levels used in this study.)  Davenport’s 2011 study, however, concluded that some of the SF-36 subscales could predict recovery (or not) from exercise. Plus, the p-value in this study (p <.07)  for the MFI/peak V02 correlation was not far off from being significant (p <.05) and the authors possibly drawing a different conclusion. Measuring MFI after the exercise, when many of the ME/CFS patients were probably still suffering and the controls were fine, might have gotten better results.

MEI VO2 peak me/CFS

ME/CFS patients are in red. MFI is on the X-axis; VO2 Peak on the Y.

It seems to make sense that a demonstrated inability to exercise would be associated with fatigue. So why is a reduced VO2 peak not correlated with some patient self-assessments of their fatigue levels?

There could be several reasons. It’s possible that ceiling effects in those assessment tools (patients score near the top for fatigue whether they exercise or not) and/or that the tools have difficulty measuring PEM could play a role. Plus, only relatively healthier ME/CFS patients are up for an exercise study.

A look at the VO2 peak graph indicates that some of the upper functioning ME/CFS patients had higher VO2 peaks than the lower sedentary controls. One ME/CFS patient – a distinct outlier – had a VO2 peak of 40 – double that of the rest of the ME/CFS patients – and far above that of the sedentary controls. High VO2 max scores are rare in ME/CFS but can occur in the young and/or particularly athletic (prior to getting ME/CFS). It was surprising to see such a distinct outlier included in the results.

Another ME/CFS patient had a higher VO2 max than all but three of the healthy controls. Some healthy controls on the other had very low VO2 maxes. Such variability underscores why two-day tests, which compare changes in individual results over both days rather than raw group scores on one day, are so much more valuable.

Snell’s 2013 exercise study found that significant differences in functional impairment and fatigue in ME/CFS showed up only after the second exercise test:

It might be concluded that a single exercise test is insufficient to reliably demonstrate functional impairment in people with CFS. A second test might be necessary to document the atypical recovery response and protracted fatigue possibly unique to CFS, which can severely limit productivity in the home and workplace.

Keller’s 2014 exercise study concluded the same:

… if based on only one CPET, functional impairment classification will be mis-identified in many ME/CFS participants.

Unfortunately, the authors of the Stanford paper did not make clear the possible confounding issues. Thankfully, they did note that two-day CPETS do have their place in ME/CFS research. The authors also stated that the next step was replicating the study with a two-day exercise study.

However, in 2007 a seminal study by Snell et al. demonstrated the value in using a two-day CPET protocol, through diminished CPET performed a day after the first.

That was helpful, but it was strange to see the authors state some ME/CFS patients have post-exertional malaise and some don’t given the central role it’s now acknowledged to play in ME/CFS.

Contemporary studies have confirmed these findings and suggested the use of a two-day CPET challenge protocol when assessing patients with ME/CFS in particular those with post exercise malaise.

That little boo-boo – that PEM is not found in everybody with ME/CFS – was compounded a bit by the researchers’ statement that all the patients completed the exercise protocol with “no adverse effects”.

All patients successfully completed a symptom limited one–day exercise protocol with no adverse events.

The authors probably meant that no serious adverse events (patient collapsed) occurred during the exercise test but didn’t make that clear and the statement could be read differently.

No Small Hearts or Stiff Arteries Found

Several studies, some of which were larger than this one, have found small hearts in ME/CFS.  (One of those studies found smaller hearts only in ME/CFS patients with orthostatic intolerance.) The small hearts are presumably caused by reduced blood flow to the heart (preload) because of blood vessel problems in the pelvis and lower body.  Other studies have found increased arterial stiffness. Neither, however, were found in this one.

Cytokines

The direct relationship between cytokines however, differed between case and controls networks supportive of a distinct cytokine inflammatory signature in ME/CFS.  The authors

Cytokine testing did, however, reveal significant differences in immune activation 18 hours after the exercise test in both patient and control groups. Ten cytokines were altered in both groups but the seven cytokines that changed only in the controls (IL-2, IL-12p40, IL-17F, LIF, TNF-α and GM-CSF) and the five cytokines (CXCL10, IL-8, CCL4, TNF-β and ICAM-1) that changed only in the ME/CFS group indicated a very different immune response between patients and controls.

Exercise provoked different immune networks in the two groups. Note VEGF at the top in the ME/CFS group at the right.

Pro-inflammatory cytokine production was still up in both groups 18 hours after exercise but in different ways. TNF-a, – a pro-inflammatory cytokine that is commonly increased in healthy people after exercise, was increased in the healthy controls but not, surprisingly, in the ME/CFS patients.

A network analysis revealed two dissimilar immune networks. IL-4 was a key player in both networks but after that the similarities ended. While IL-5, TNF-a and IL-2 played major roles in the healthy controls immune response, CXCL10, vascular endothelial growth factor (VEGF) and IL-15 played major roles in the immune response of the ME/CFS patients.

VEGF was not mentioned in the discussion section but it’s popped up in several ME/CFS research studies and plays a major role in Dr. Shoemaker’s conception of mold illness.

Discriminating Factors?

The authors stated that “Compared to resting cytokine profiles, our study highlights that post-exercise profiling could have greater value in discriminating case status than resting parameters.” Another statement in the paper, however, suggested that post-exercise cytokine levels were not particularly helpful in discriminating ME/CFS patients from healthy controls.

In the results section, the authors’ statement that, “Cytokines following exercise had nominally better discrimination (greater kappa value) than resting parameters and absolute dynamic change”, suggested that exercise may not have enhanced the ability of cytokines to separate healthy controls from ME/CFS patients much.

Two immune factors, CD40L and CXCL10, best distinguished the healthy controls from the ME/CFS patients. I couldn’t find similar evidence of CXCL10 in past ME/CFS research but this is the second time it has shown up in Montoya’s studies.

Decreased CD40L levels were also found in Light’s 2010 exercise study, but increased, not decreased levels were found in ME/CFS patients’ mast cells in Gradisnuk’s 2017 study. The soluble CD40L receptor was also increased in ME/CFS patients three years after a Giardia infection.

CD40L is primarily found on activated T-cells. (Defective CD40L receptors have been associated with something called hyper IGM syndrome which is characterized by defective CD40 signaling. People with hyper IGM syndrome “have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections.”)

CXCL1 could end up being an important chemokine; its levels decreased with exercise in this study in both the ME/CFS patients and the healthy controls, and the study authors reported that it demonstrated “high relative centrality with the network participants with ME/CFS”. Increased CXCL1 levels were associated with more severe ME/CFS patients in Montoya’s recent cytokine study.

Another chemokine, CXCL10, (chemokines have been up in ME/CFS recently) which plays a role in autoimmune diseases, diabetes and inflammatory bowel disease, figured prominently in the ME/CFS immune network.  CXCL10 also clears the way for the entry of natural killer cells and T lymphocytes into the brain. Increased levels of CXCL10 have been found in the spinal fluid of ME/CFS patients.  CXCL10 was also increased in the more severely ill in Montoya’s recent cytokine study.

Researchers often produce convoluted, hard-to-understand sentences and are hardly expected to be masters of the English language, but grammatical errors abounded in this paper.

  • “This is consistent with previous findings indicating that a failure to reduced levels of CD40L post exercise is associated with increased symptom flare post a bout of moderate exercise.”
  • Unlikely CD40L, in univariate analysis separately by cytokine, CXCL1 decreased with exercise in controls and cases.”
  • “Further supportive of an immune mediate pathway in ME/CFS, we found CXCL10 played a central role in the cytokine network and contributed to case discrimination when combine with delta change in IL-4, G-CSF, IL-1β, IL-7 and CD40L.”

Conclusion

Despite some of the issues it was good to see a relatively large – for this field anyway – study examining the effects of exercise on immune parameters. The study demonstrated that exercise provoked markedly different immune responses in ME/CFS patients and healthy controls and did highlight some interesting immune factors. It did not find evidence of vascular stiffness or small hearts.

It’s not clear what to do with yet another short-term cytokine study, though. It does suggest the immune system is involved but we’re continuing to see a lot of variability in cytokine studies. Since cytokines don’t necessarily point to cause because they can be provoked in so many ways, their main value is in potential treatments. Cytokine-busting drugs are now plentiful and will only get more plentiful in the future but we need clear, consistent results stating that X or Y cytokine plays a major role in ME/CFS. TGF-B is the only cytokine thus far to be somewhat consistently abnormal in ME/CFS.

More intensive studies do seem to be getting better results. Montoya’s recent large cytokine study showed a strong correlation between severity and increasing cytokine levels. Younger’s “good day/bad day” study got excellent results and was refunded. With regards to exercise, this study’s results will probably be quickly superseded by more intensive efforts by Nancy Klimas and David Systrom.

Dr. Klimas has created a very large database of cytokine and other results taken from testing done at 8 time points, as I remember, before, during and after exercise. She has enough data to use those results to devise treatment options that she hopes will knock out post-exertional malaise.  Dr. Systrom, funded through a donation made to the Solve ME/CFS Initiative (SMCI), is using invasive (catheter) testing to measure many different factors at different places in the body as ME/CFS patients exercise.

Hopefully these studies will provide a clearer path.

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