The IACFS/ME Conference Reports # V
Whacking Those Patients - The Exercise Studies
Reno, Nevada: March 12-16, 2009
By Cort Johnson
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Whack Those Patients!
Two years ago repeat exercise tests at the 2007 Fort Lauderdale IACFS/ME showed
ME/CFS patients falling apart metabolically on their second exercise test. Dr.
Whistler was impressed enough with her results to call for stress tests of one
sort or another to be used in every study. One of the most intriguing themes of
the conference is the degree to which repeat exercise tests are beginning to
pervade the research arena.
More Stress = Better Results: The Call Goes Out to Whack ME/CFS Patients
Natural Killer Cell Function is Depressed in Gulf War Illness. Toni Whistler,
Mary Fletcher, W. Loneragan, S. Vernon and Nancy Klimas.
Toni Whistler was excited – I could hear it in her voice. She was reporting on
natural killer cell (NK) functioning in Gulf War Syndrome (GWS) patients. She
had put them through an exercise stress test and then measured their NK cell
functioning. She wanted to make it clear how important she felt exercise tests
were. She stated it twice. Both times I could hear her voice rise as she
emphatically stated that "challenge studies (e.g. exercise tests/stress tests)
are critical for finding differences between chronic fatigue syndrome
patients and controls;" i.e., to get strong results you’re probably to have to
whack
your patients pretty hard.
Natural killer cells man the lines of our first immune response. They troll
about inspecting cells to see if they’re defective or infected or cancerous. If
they find a bad cell, they kill it and raise the alarm. We know the natural
killer cells are not tracking down and killing infected cells like they should
in this disease and it appears (unfortunately) that, at least in some patients,
they’re not tracking down cancerous cells either. This study took natural killer
cell research to the next level; they examined the gene expression (gene
activity) before and after exercise to see if different genes were active in the
GWS and healthy controls.
The need for a stress test of some sort is really no secret - the research
community is finally catching on to a pattern that's been obvious for some time
now. Studies that measure patients at baseline (at rest) often do not have
positive results but studies that somehow stress whatever system they’re
studying often do. Dr. Whistler also underscored a broader need that came up
again and again during the conference and reached a peak with Dr. Vernon’s
address - the need for research standards in this disease.
Why do an exercise test for a study on natural killer cell functioning?
Apparently NK cells spill out of the lymphoid organs (lymph nodes, spleen) and
rush into the blood when we exercise. They obviously do that for a reason. Staci
Stevens has suggested that the post-exertional malaise in ME/CFS could be due to
immune dysfunction . One wonders if that immune dysfunction somehow involves
malfunctioning NK cells.
What are they trying to get at? One suspects gene networks that influence
natural killer cell activity. Dr. Vernon recently published a paper suggesting
that immune cells network differently in chronic fatigue syndrome patients.
Instead of the efficient, streamlined immune networks found in healthy people
she found large fragmented networks in ME/CFS patients. Essentially those large
well integrated networks of immune cells that work together to produce a
powerful immune response just aren’t found in many ME/CFS patients.
This study found that 49 genes involved in NK cell function had increased
activity in the healthy controls but only nine genes had increased
activity in the GWS patients. This suggests that a big chunk of the essential
gene activity needed for a healthy NK cell response is just not occurring in GWS
(or ME/CFS). (Dr. Whistler stated that the two groups are essentially similar)
Interestingly, the activity of the gene for perforin - the shells that make up
the NK cell's heavy artillery - was lower in GWS patients. Low perforin levels
have been a hallmark finding in ME/CFS.
A Natural Killer Cell Disease? The Fletcher/Klimas team in Miami started
this work about 20 years ago and the closer they’ve looked the more they’ve
found. Thus far they’ve been the only research team to take this on. (Why the
CDC has never incorporated NK cell studies into their research is puzzling. They
have never gone so far (so far as I can tell) as to measure the activity of a
single natural killer cell in all their studies). Now the Whittemore-Peterson
Institute is stepping into the gap. Later in the conference Dr. Mikovits will
pinpoint a defect in the natural killer cells in Dr. Peterson’s Reno cohort that
could prevent them from identifying infected cells . Natural killer cell
problems appeared to be at the heart of the immune dysfunction in many ME/CFS
patients.
Collaboration Works! This study was an excellent example of the kind of
collaborative effort Dr. Vernon has been proposing (and initiating at the CAA).
It included researchers from the CDC (Dr. Whistler), the CFIDS Association of
America (Dr. Vernon) and Fletcher/Klimas team in Miami. Given Dr. Whistler’s
affiliation with the CDC – the same group that relegated the post-exertional
fatigue symptom to irrelevance in their latest definition - it was startling to
hear her make the call for more exercise stress tests. One wonders how far her
views will carry at that group.
Exercise and Hormones in Spain
Suarez, A, Javierre, C. Alegre, J. etc. al. Hormonal Evaluation in the Chronic
Fatigue Syndrome
This group loaded the deck with their patients: they didn’t just work them; it
sounded like they almost beat them to death. If I got this right - and it wasn’t
easy figuring it out - instead of exercising for two days they had their
patients exercise for three days straight. Instead of working them to exhaustion
once a day they worked them to exhaustion three times a day. After each
workout they were allowed to rest for 3 minutes then back they went pedaling
until their legs went numb again. (Presumably those legs very quickly went numb
the second and third times). Afterwords Dr. Suarez told me they had some very
sick people participating….If they weren’t very sick going in they certainly
must have been afterwards.
In any case these chronic fatigue syndrome patients did not show reduced
exercise capacity (VO2 max) relative to the controls on the first day, the
second day or the third day! (I started getting a sinking feeling in my stomach
– had the Pacific Fatigue Lab research already been upended? Was another dream
taken away so soon? If so - this would surely be a record! I had just talked to
Eleanor Stein whose small study had shown the same thing - no repeat exercise
differences in her study.)
These patients did, however, show reduced cortisol levels; in fact, every day
the ME/CFS patients had lower and lower levels of cortisol relative to
the controls. This is intriguing since cortisol does control glucose uptake
(i.e. energy) to the muscles. It ensures that the muscles get the energy they
need during stressful situations like exercise. These ME/CFS patients were
getting less cortisol precisely at the point they most needed it. Other hormonal
indicators such as growth hormone, prolactin and ACTH, on the other hand, were
normal.
There’s plainly no getting away from cortisol in this disease. While it’s only
mildly low, it’s still mildly low again and again and again. This study suggests
that cortisol levels in ME/CFS patients begin a bit low and they tank during
exercise.
NOOOOOOO! It’s Happening Again! (Or is it?)
Tolerance to Repeated Maximal Exercise in ME/CFS. E Taub. E. Stein and B.
MacIntosh.
I came across this poster before Dr. Van Ness gave his presentation (see below)
and shot Dr. Stein a rather angry look. How could you, I thought? How could you
debunk this great theory? How dare you? Objectivity was definitely thrown to the
winds. Five females with ME/CFS bicycle to exhaustion two days in a row and
their VO2 Max results don’t budge…a
t all. They were as strong metabolically the
second day as they were the first day. This looked to set a record for hopes
dashed - just in the last month I’d sent out a newsletter suggesting that the
repeat exercise studies could be ‘IT’ in this disease - and now this….
After talking to Dr. Stein, though, it was hard to get upset with her. She,
herself has had ME/CFS for many years. She’d done the study hoping and expecting
that the results would be different. She assured me that all the participants
had had strong post-exertional fatigue but that they just didn’t have ‘metabolic
dysfunction’.
This means that post-exertional fatigue is not necessarily synonymous with
metabolic dysfunction - you could be wiped out by exercise and still not have
‘metabolic dysfunction’. (One wonders if the opposite is true as well - I know
of one patient who was able to exercise even when his VO2 levels were quite
low.) When I asked Staci Stevens about the study, she said the participants had
had pretty high VO2 maxes to start off with – and that could have made a
difference.
The Metabolic Subset
A Diagnostic Test for the Identification of Metabolic Dysfunction. J. VanNess,
Staci Stevens, K. Kumasaka, H. Singh, et. al.
The title says it all; ‘A Diagnostic Test for the Identification of Metabolic
Dysfunction' – not chronic fatigue syndrome. Despite the CDC's effort
to expand the parameters of this disease (‘unwellness syndrome’?) we are slowly
seeing the beginning of the end of chronic fatigue syndrome name and the
breaking up of the disease. The research community appears to sense that the era
of ’subsets’ is upon us.
In his opening remarks HYPERLINK Dr. Peterson stated that the search for A
biomarker is over, that it’s all about subsets now. The Whittemore-Peterson
Institute believes they’ve found immune biomarkers for a subset of patients. If
they have, they’ve cut a whole chunk of ME/CFS patients free from the chronic
fatigue syndrome label. Both Staci Stevens and Dr. Klimas implored the CDC to go
after subsets at the public review of the CDC’s draft strategic plan.
The Pacific Fatigue Lab’s presentation was about nailing down that metabolic
dysfunction subset, those patients whose metabolic tests undergo inexplicable
declines during a second exercise test. The Pacific Fatigue Lab presented data
from a broad range of results from their studies and disability evaluations, the
Montoya Valcyte Study and some patients from a practitioner in Ithaca, New York.
About 40% of their group, 40% of patients from Ithaca (7 patients), 55% of Dr.
Montoya’s patients and about 70% of people doing disability evaluations at the
PFL met the threshold for ‘metabolic dysfunction’. At this point it appears that
somewhere around half the patients thus far tested have this problem.
The percentages may be higher. Dr. Van Ness remarked on the possibility that a
‘physiological floor’ could be obscuring some of the results. Apparently some
people who have very low VO2 max scores the first day had similar scores the
next day as well. This could mean there’s a floor you can’t get lower than (and
still be alive?).
The tests are not necessarily representative of the population at large; the PFL
won’t do tests if you’re too ill and there are presumably a lot of healthier
patients who have considerable fatigue and impaired functioning who don’t fit
into the high EBV or disability group.
Unfortunately the Pacific Fatigue Lab has been another casualty in the NIH Grant
meat grinder; they spent six months or so putting together a several hundred
page grant application and were denied - in no small part because they weren’t
allied with a major institution. Staci Steven suggested they probably won’t
undergo that process soon again.
Dig Deeper: Check out ‘Cracking the Foundations’ for more on the Pacific Fatigue
Lab’s Work
NOOOOOOO! Is it NO after all?
A Diagnostic Method for the Evaluation of Chronic Fatigue Syndrome? A Suarez, C.
Javierre, T. Roig, et. al.
This was just a single exercise test but that’s all it took; 37 chronic fatigue
syndrome (ME/CFS) patients blew their healthy counterparts away with higher
(much higher) nitrate levels in their blood (but not lactate or glucose) levels
after a single exercise test.
This was definitely new. Several studies have looked for abnormal lactate levels
– a common finding in muscle dysfunction - but their findings have been
inconsistent. But now nitrates show up – in spades - in ME/CFS patient’s blood.
Not only that but it’s a very strange finding.
Nitrate in the blood is derived from nitric oxide (NO) which the endothelial
cells lining our blood vessels produce in order to increase the size of the
blood vessels (and increase blood flows). These findings then suggest that these
patient’s blood vessels were too open. Usually in disease it’s just the
opposite they’re too narrowed.
Nitrates are often given to heart patients in order to increase blood vessel
dilation and improve blood flows to the heart. They are used to increase
exercise capacity! but here we have these exercise-impaired patients with
higher than normal nitrate levels!
Interestingly, in Italo Biaggoni’s NIH-funded study he is looking for signs of
the opposite situation - decreased endothelial nitric oxide production.
It’s hard to know what to make of this little study. Will it simply be another
odd blip on the ME/CFS radar or will it amount to something? Only time will
tell.
Dig Deeper! For More Reno IACFS/ME Conference Overviews