The search for
a test (part one)
By Renee Brehio and Carol Sieverling
of chronic fatigue and immune dysfunction syndrome (CFIDS) involves eliminating all other possible causes,
a lengthy process that is often expensive and painful. A proven diagnostic test would help erase doubts
that CFIDS is real, as well as help physicians better identify the illness, begin treatment earlier and
possibly shed some light on the cause.
For years researchers have been chasing this elusive Holy
Grail. Most of the hunt has focused around trying to find a biochemical abnormality in CFIDS patients-something
that can be found simply in urine or blood samples. On the surface, it seems as if this should be a fairly
easy task. It is obvious that many of the body systems of persons with CFIDS (neurological, immune and
endocrine, just to name a few) do not function in a normal fashion. So why do we not have a test yet?
One reason lays in the very existence of those multiple defects. Many different abnormalities
have been found to be involved in CFIDS, so research needs to sort out the ones that could be tested for
easily and reliably. There may be subgroups or categories of CFIDS patients, so some tests might not be
applicable for widespread use. In addition, biochemical changes brought about by CFIDS may not occur until
later in the illness, making it difficult to develop a test that would work from onset.
are a number of different theories on diagnostic methods, and the good news is that recent research seems
to be bringing us closer to the ultimate goal. The following overview covers a theory in the confirmation
phase (RNase L) and two pilot studies (RNA abnormalities and 5-HIAA).
RNase L: an unusual enzyme
major avenue of promising
research into a diagnostic test has been the RNase L antiviral pathway. When a virus infects a cell, the
interferon pathway is activated. To repulse the invader, an enzyme is activated that destroys the RNA
(ribonucleic acid) within the virus, effectively eradicating the genetic code it needs to reproduce. This
enzyme is called RNase L.
PWCs may have a different form of RNase L than individuals who do not
have CFIDS. The known form of RNase L weighs 80 kilo Daltons (kDa). Two different research labs, in the
United States and France, have found a new 37 kDa form of RNase L in CFIDS patients. This could mean that
PWCs have a defective disease-fighting enzyme. The more of the defective, low molecular weight RNase L
that is present, the more severe the CFIDS is clinically.
The lower molecular weight RNase L lasts
longer in the body and becomes damaging. Normally, once the RNase L has destroyed the viral RNA, it switches
itself off. The problem with the lower weight RNase L is that it takes much longer to shut down. It continues
to be active, even more so than the 80 kDa form, interfering with other functions of the cell. The antiviral
pathway actually begins to consume adenosine triphosphate (ATP), the cell's energy source, possibly leading
to some of the symptoms of CFIDS.
Three researchers--Dr. Robert Suhadolnik in the United States,
Dr. Bernard Lebleu in France, and Dr. Kenny DeMeirleir in Belgium--have led the exploration into RNase
L as a possible diag-nostic test for CFIDS. In a study that was funded by The CFIDS Association and published
in the February 2, 2000, issue of the American Journal of Medicine (delayed from December 1999,
as reported in the last issue of the Chronicle), Lebleu and DeMeirleir tested the blood of 57
CFIDS patients, 11 fibromyalgia patients and 28 healthy controls for RNase L. They found that the CFIDS
patients had a much higher percentage of the defective form of the enzyme than the other groups. This
is important because it suggests that at least some cases of CFIDS may be able to be differentiated from
Another interesting finding from the study was that only two of the 28 controls had
high ratios of the 37 kDa RNase L, but both had regular contact with CFIDS patients. This may suggest
that CFIDS is linked to a pathogen that is transmittable.
How accurate is the test? Dr Lebleu and
Dr. Suhadolnik tested the same group of 90 CFIDS patients as well as a control group for 37 kDa RNase
L, using slightly different but comparable methods. Dr. Suhadolnik correctly identified 93% and Dr. Lebleu
correctly identified 100% of the CFIDS patients.
Despite this high accuracy, the researchers emphasize
that the test cannot yet be considered a diagnostic marker. People with other illnesses may also have
a high percentage of the defective enzyme. In addition, not all PWCs in recent studies were found to have
37 kDa RNase L, which may mean that only a particular subgroup of patients experience this problem, and
that group might need to be defined for the purposes of clinical research. Further studies are underway
to establish whether the RNase L enzyme dysfunction in CFIDS is associated with a particular stage of
the illness or if it fluctuates over time.
RNA: the genetic poker game
may be able to find clues to a diagnostic test in research being done with respect to related conditions,
such as Gulf War illness. In the summer of 1999, Dr. Paul Cheney, a pioneering CFIDS physician practicing
in North Carolina, read a newly published study ("RNAs in the sera of Persian Gulf War Veterans have segments
homologous to chromosome 22q11.2," Clinical and Diagnostic Laboratory Immunology, May 1999: 330-335)
and envisioned a possible diagnostic marker for CFIDS.
Test subjects included three Gulf War veterans,
seven healthy control subjects and two people with active polio virus. The researchers probed their blood
for both RNA and DNA. They found thousands of different-sized RNA segments floating around in the blood
of the veterans, a small amount in the polio subjects and none in the healthy controls. The researchers
called this "voyager RNA" since it travels around in the blood outside of the cells.
Much of this
voyager RNA in the veterans tested was abnormal or mutated, and it appeared that all of the veterans had
the same mutations. The researchers then isolated the mutated sequence in the RNA and examined it in detail.
They began recognizing certain pieces, which they realized all came from part of chromosome 22. It appeared
that a section of chromosome 22 had been sliced up, rearranged, pieces from somewhere else inserted and
the whole thing reconnected. In short, it was confirmed that a section of chromosome 22 was altered in
exactly the same way in all three veterans.
Since these veterans had symptoms identical to CFIDS,
Dr. Cheney began testing CFIDS patients and almost all had this same aberrant RNA segment. This suggests
that the veterans and the CFIDS patients have the same illness and that the aberrant segment of RNA could
be a diagnostic marker. Dr. Cheney suspects that this marker only appears well into the illness, and will
not be found close to onset. He also believes that the amount of aberrant RNA in the blood serum may correlate
with illness severity.
Why would patients with CFIDS and GWS have an aberrant piece of RNA, and
why would they all happen to have the same one? Dr. Cheney suggests that when we are faced with an extreme
threat to our health, our bodies may break up some of our DNA and shuffle the pieces, trying to find something
to help the healing process. These segments float around in the blood on their way to other cells to make
more copies, and may show up on the test more easily because there are so many of them. The segments the
body chooses may help it heal, or may be useless and not help or hurt. These segments may be a marker
because everyone with the same illness will eventually shuffle their DNA in the same way.
possibility, according to Cheney, is that the body shuffles its DNA and creates a metabolic toxin. If
the segment is extremely poisonous it will destroy the cell in which it was created, thus destroying itself.
The real problem is the minor toxins, the ones that make you sick but won't kill you. If your body shuffles
out enough of these segments, the toxins can keep you from getting well.
More research is needed
to understand how these segments of RNA are related to CFIDS, but Dr. Cheney believes it is a strong candidate.
"While it would be a genetic marker, it is important to understand that it is not one that we are born
with," he says. "It is one that our body creates in response to illness."
5-HIAA: making news
possibility for a diagnostic
test that has gained quite a bit of media attention is 5-HIAA, a metabolite of serotonin, a neurotransmitter
found in the brain.
Researchers at Georgetown University who originally had studied the effect
of ENADA (NADH) on a small group of CFIDS patients noticed that there were some differences in the concentrations
of certain chemicals in the urine of PWCs versus the normal controls. When they performed a follow-up
study, they found that 75% of the patients showed elevated levels of 5-HIAA.
Serotonin is a neurotransmitter
known to be responsible for mediating mood, sleep, perception and appetite. It is also present at sites
of inflam-mation in the body, which may mean that it plays a role in causing joint and muscle pains in
PWCs. When treated with NADH, 70% of the patients returned to a "normal" range of 5-HIAA versus 30% of
the controls who received a placebo.
"The measurement of 5-HIAA may not only serve as a useful
predictive marker of disease activity in CFIDS patients but also may provide an objective measure of improvement
following therapy with NADH," suggests Dr. Joseph Bellanti, lead researcher on the study.
results of the Georgetown study will soon be published in the Annals of Allergy, Asthma & Immunology.
Keep in mind, though, that this study was conducted with a very small number of patients-only 20. Much
more work will need to be done to confirm HIAA as a diagnostic marker. The researchers themselves suggest
that a larger study should be done to investigate serotonin's role in CFIDS and how levels of 5-HIAA correlate
with disease activity.
The next issue of the Chronicle
will contain part two of this
article series on diagnostic tests for CFIDS. Part two will focus on developments occurring outside the
United States, including the work of the Newcastle Group in Australia, which has been conducting research
on abnormalities in blood and urine that could be used to differentiate PWCs from patients with other
Brehio is Director
of Communications for The CFIDS Association of America. Carol Sieverling is leader of the CFS/FM Support
Group of Dallas/Fort Worth.
Why RNA is important
Very similar to DNA (deoxyribonucleic acid), which forms the genetic code,
RNA (ribonucleic acid) plays more of a facilitator role. RNA controls the manufacture of proteins in all
living cells. This is absolutely crucial to our functioning, since proteins are essential for growth,
the building of new body tissue, and the repair of injured or broken-down tissue.
USA TODAY chronicles life with "phantom
to USA TODAY, the nation’s most-read newspaper, for treating chronic fatigue syndrome (CFS) with
respect and revealing the devastating effect it has on sufferers’ lives. In "Real life with a ‘phantom
disease’: More sufferers don’t mean more answers about chronic fatigue" (January 13 issue), Kathy Fackelmann
takes a more personal look at the illness than most reporters have to date.
Fackelmann notes that
despite mounting evidence that CFS is more widespread than initially thought, many people, including doctors,
still "write off" individuals with the illness. She then builds a compelling argument for why CFS should
not be trivialized, starting with a mention of the recent study from DePaul University that debunked some
of the most prevalent myths about the condition (see Nov./Dec. 1999 issue of the Chronicle, "
The almost full-page
that a wide range of people can be affected by CFS. The patients interviewed for the article were Terry
Hedrick, a PhD who has served as director of research for the General Accounting Office; Barbara Brock,
an African-American former nurse; and Rebecca Moore, a 22-year old who became ill when she was 15.
Fackelmann makes no bones about the untenable condition PWCs are in. She points out that there
is no diagnostic test or effective treatments, and doctors can only partially relieve the symp-toms. She
also emphasizes the additional setback patients have faced recently--loss of precious time searching for
a cure due to the CDC misappropriation of research funds. The article ends as it begins, focusing on the
human implications. "For people suffering from chronic fatigue syndrome, the [CDC] scandal represents
a personal blow."
Positive coverage of this nature usually doesn’t happen by accident. It needs
a catalyst--a significant piece of research or event—to set it in motion. In this case, the DePaul study
gave the media some new fodder. A positive story also needs a champion that can help the reporter get
to the heart of the matter. The CFIDS Association of America worked closely with Kathy Facklemann to help
her understand the nature of CFIDS, interview credible patients and physicians and represent the issues
accurately and fairly.