The search for a test (part one)

Editor’s Note: The following article is reprinted with permission from The CFIDS Chronicle, Vol. 13 No. 1 Winter 2000.

Currently, the diagnosis 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 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.

There 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 tow pilot studies (RNA abnormalities and 5-HIAA).

Rnase L: an unusual enzyme

One 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 diagnostic 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 fibromyalgia.

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

We also 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 (“RNA 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 poliovirus. 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 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 may be a marker because everyone with the same illness will eventually shuffle their DNA in the same way.

Another 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.”

HIAA: making news

One new possibility for a diagnostic test that has gained quite a bit of media attention is 5HIAA, 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 inflammation 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.

The 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.

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