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Winter 2003 

Chronicle Q & A: CDC shifting to clinical studies
The U.S. Centers for Disease Control and Prevention (CDC) runs the world’s largest CFIDS research program. Last year, the CDC spent nearly $9 million on programs to study the illness and educate health care providers about diagnosis and treatment. Yet the CDC remains highly controversial in the CFIDS community. From 1995–98, officials diverted $12.9 million earmarked for CFIDS research to other programs. The funds are being paid back to the CFIDS program over the course of several years.

In this interview, Dr. William Reeves, head of the CFIDS program at CDC, talks about current research underway at CDC — and discusses the future of the CFIDS program in light of current terrorist threats facing the nation.

Q. What are the CDC’s main goals for CFIDS research?

A. We have several objectives. The first is to estimate the magnitude of the public health problem that CFS (another term for CFIDS ) poses in the United States . We accomplish this by surveillance. Information from surveillance is important for health care providers and is critical to determine allocation of health resources.

Our second objective is to try to determine if CFS represents a single disease or is a common response to more than one insult. The analogy I like to use is arthritis. By definition, arthritis is hot, tender, swollen joints. This can be caused by autoimmune diseases, like rheumatoid arthritis or lupus; by repetitive stress or other injuries; or by infection. They all present the same way as far as the patient is concerned, but their causes, treatment and prevention are completely different. I don’t believe it is clear whether CFS is a “thing,” or if it’s more like arthritis, a common final response to quite different causes.

Our third objective is to determine the pathophysiology of the disease; in other words, how does CFS affect normal body processes? The fourth is to identify causal agents, risk factors and diagnostic markers for CFS, and the fifth is education. We’re doing some of that now with The CFIDS Association.

Our entire program reflects CDC’s mission to prevent and control disease. But until we figure out risk factors, diagnostic markers, and what causes CFS, we really can’t develop effective prevention and control.

Until recently, the CFS program has emphasized surveillance. However, I think it’s pretty clear from our studies, and from other population-based studies (such as those of Dr. Leonard Jason ), that we have a pretty good idea of the magnitude of the problem. It’s somewhere between half a million and a million adult Americans with the disease. Although CFS affects adolescents, it is much less common than among adults.

Q. You have cancelled a nationwide study on the prevalence of CFIDS. Why?

A. The main reason the study was put on hold was Sept. 11. We had started a pilot study about three months before and we ended about three months after. We encountered some problems following the tragedy. People weren’t so willing to answer personal questions — and we had some real worries that 9-11 might have changed the occurrence of CFS. We’re doing some analysis to see whether that has happened. We did screen more than 7,000 people in eight areas around the country, which should yield some interesting data.

Cost and staff resources were also a big consideration. It didn’t look from the pilot study as if our estimates of occurrence would change substantially. So it didn’t appear to justify the $3 million or $4 million to complete it. We felt the funds and scientific effort would be better applied to other priorities. As an aside, The CFIDS Association collaborated in coordinating the pilot survey and was responsible for the clinical evaluation component.

Q. So your emphasis is starting to change?

A. We’re moving much more into pathophysiology and clinical studies now. We have some incredible opportunities to study groups of people with CFS in ways no research group has been able to do before.

Much of this has been possible because of our surveillance program in Wichita , Kan. Wichita is like a poster city for mainstream America . We screened 20 percent of the entire city’s population for CFS and followed 4,000 subjects annually over four years.

We have identified a representative sample of people with CFS, of people with not-quite CFS, and with CFS with various co-morbidities, like major depressive disorder. They represent the general population— we are not limited to patients with CFS who are seeing health care providers. If you only look at those folks, you don’t get an accurate picture of the scope of everyone suffering from CFS.

We now have the opportunity to study these people clinically. And that’s what we’re doing. We have invited all subjects we identified in Wichita who have ever had CFS; those who would have had CFS except that they have exclusionary depressive disorders; people with severe chronic fatigue who didn’t quite meet the case definition for CFS; and a group selected from the general population, who are matched by age, race, sex and body mass index. It’s about 400 people, including seventy-some with CFS. They are representative of the Wichitapopulation.

We are inviting them for a two-day hospital stay, during which they’ll have a complete battery of neuroendocrine and immune function studies. Response has been excellent so far and most are volunteering to participate. Since most people with CFS report sleep problems our subjects also have formal sleep studies. These include two overnight sessions and multiple sleep-latency tests. Evaluating sleep at night, one can tell a lot about sleep problems. But you also have to look at people during the day, too. That’s called sleep latency. You look at how quickly you can nap during the day, how easily you can stay awake in a darkened room — things that are influenced by different sleep disorders.

Most people with CFS also report problems with concentration and memory. People in the Wichita clinical study are also undergoing formal mental function (cognitive) studies, using a group of tests called the CANTAB. In order to separate interactions between CFS and depression, we are assessing subjects’ psychiatric status.

It’s increasingly clear that neuroendocrine and immune function reflect physiologic adaptation to accumulated events over one’s life. So, we’re doing a rather complete measurement of the subjects’ lifetime stress history and their reactions to stress.

Finally, all of those with CFS, and the controls, will have tilt-table testing done. The study is about as comprehensive as we could possibly make it.

Q. What other clinical studies are underway?

A. The big ones are modeling studies. In modeling studies, you enroll subjects who have been exposed to something that you know will cause symptoms of CFS and measure how the body reacts. We’re doing two studies with Emory University , and another one in Australia (see box).

All of our studies include cutting-edge laboratory tests using gene expression and proteomics. Gene expression measures activity of messenger RNA. We are able to describe the activity of 10,000 to 30,000 genes at a pop — which ones are “on,” which ones are switched “off,” which ones are turned up a little and which ones are turned down. Differences in gene expression profiles can help to distinguish between people who have CFS and those who don’t.

In contrast, proteomics measures all the proteins that exist in a sample of someone’s blood. Genes code for the creation of proteins, so proteins can only be there if the genes call for them. But there is not a one-to-one relationship. Proteins have their own cycles, and regulate each other, to some extent independently of gene expression.

Q. Why are these tests important?

A. There are several benefits. First, if we can identify a pattern of gene expression that distinguishes people with CFS from controls, we will have a diagnostic test for CFS.

In addition to diagnosis, gene expression analysis provides a window into the pathophysiology of CFS. What protein or cell pathways are these over- or under-expressed genes part of? How might these relate to CFS? While it doesn’t really matter what the particular gene or protein is for a diagnostic test, it makes a big difference when you’re looking at what may be causing CFS or searching for targets amenable to therapy.

The two sets of data together can be powerful. We’ve done some preliminary work that shows we can separate people with CFS from non-fatigued controls.

Q. What new studies are in the pipeline?

A. We are already thinking about the next clinical study. We have done everything we can imagine in the Wichita clinical study — but we haven’t done any of it in great detail.

For instance, for the neuroendocrine measurements, we’re only collecting blood once. This will be less disruptive to cognitive and sleep studies. Detailed measurements of neuroendocrine function would have an IV in the subjects over one or two days and they would be sampled constantly in conjunction with application of various stimuli, perhaps done in conjunction with brain imaging.

The comprehensive set of measurements we’re collecting in Wichita will tell us what we might need to examine in more detail. It’s a starting point. We will do a much more detailed study based on what we find.

Q. Are you cutting back on anything?

A. Surveillance, as I said before. And we’ve suspended our efforts to identify infectious agents as causes of CFS. It is clear from studies that we and other people have done that none of the infectious agents we know of are the direct cause of most cases of CFS. We’ve recently completed a comprehensive set of studies to identify novel or previously unknown infectious agents in CFS — there are ways to do that — and no infectious agent is significantly associated with CFS. Clearly, some people develop CFS following an acute infectious illness such as mononucleosis (Epstein-Barr virus) but this is not the case for most people with the CFS. We believe it will be more productive to focus on clinical studies and searching for markers. This may lead us back toward an infectious agent, at which point we’ll look again.

Q. Has the funding scandal and payback helped raise CFIDS awareness at CDC?

A. I honestly think that CDC has been very supportive and enthusiastic about the CFS program and about the findings.

Did it raise the profile of CFS? It certainly did that, and the breadth of our current program reflects the “jump-start” restoration of the funds provided. However, and more importantly, it catalyzed the implementation of improved management and accounting procedures throughout CDC.

Q. What about the new emphasis on bioterrorism in the Bush administration? Will it erode the budget forCFIDS?

A. As world events have shown, the emphasis on bioterrorism is critical to national security and CDC must be a pivotal player in these efforts. I don’t really think it will cut into our budget. CDC support, interest, and involvement in CFS hasn’t gone away.

Although I truly don’t think the budget will be cut, I do worry about possible loss of focus on the overall CDC mission. Many issues of homeland security such as smallpox, anthrax, and chemical agents are related to programs at CDC. I’m concerned that issues of terrorism could dilute attention from CDC’s core mission. Things like influenza immunizations, childhood diarrhea, eradicating polio, cancer control — and CFS.

For more information on the CDC’s research program for CFIDS , check the CDC Web site at http://www.cdc.gov/ncidod/diseases/cfs/index.htm.

These studies are all taking advantage of new technologies that can probe deeper, further and more accurately into the development of CFIDS. Researchers say they are very hopeful that the new tools may unlock mysteries that have so far eluded them.

“We’re very jazzed about these studies,” says Dr. William Reeves, chief of the CDC’s CFIDS research program. “To me, they’re the most exciting thing going in this field.”

The first study is based in Australia . Researchers there are looking at the development of CFS in people who are infected by viruses that cause several different diseases, including Ross River Virus, Q Fever and Epstein-Barr Virus.

It’s well known that a percentage of people who contract these viruses will go on to develop CFS symptoms. By identifying these people early in the development of their illnesses, researchers will be able to track the changes to the patients as they occur and predict who will develop CFS.

The Australian study is using a testing tool called the gene expression microarray. Researchers take samples of genetic material called messenger RNA in the blood of patients, then create a “biochip” that shows the status of tens of thousands of genes. The biochip can tell which genes are “expressing”— that is, which ones are switched on to create proteins and which ones are not.

Researchers are looking for patterns. If people with CFIDS have similar gene expression patterns, the microarray test could be used to help diagnose people with the disease. This would be the first sure-fire diagnostic test for CFIDS .

Early results are promising, according to Dr. Suzanne Vernon, a microbiologist and head of the CDC’s gene expression program for CFS. Can the microarray tell the difference between people with CFS and others? “The answer is: yes it can,” Vernon told Smithsonian magazine. Vernon says she believes the microarray will someday become a routine diagnostic tool for CFS.

Other studies also use microarray technology. In one taking place at Emory University in Atlanta, researchers are tracking the development of CFIDS in patients infected with hepatitis C virus who receive treatment with interferon alpha — a drug known to produce symptoms consistent with CFIDS. This study also is using new-wave brain imaging technologies such as functional magnetic resonance imaging (fMRI) scans. Unlike regular MRIs, which provide a snapshot image of the brain, fMRIs look at the changes that occur in the brain over a period of time. This gives researchers a better look at how brain activity differs in people with CFIDS.

Emory is also working with the CDC on a study of how the release of Interleukin 6 (IL-6), a protein produced by blood cells and implicated in the development of CFIDS. This study will incorporate the microarray technology — as will the follow-up clinical studies now underway in Wichita, Kan. The IL-6 study is also funded in part by The CFIDS Association of America.

Based on data from a four-year surveillance study of residents in Wichita, Kan. , CDC officials have been able to calculate the amount of lost productivity among people with CFS who can no longer work. Dr. William Reeves, head of the CDC’s program for CFS, said the figure is still being refined — but hinted that “it’s a big, big number.”

“This is the first time we’ve really tried to look at the economics of it,” Reeves says. “We can finally measure the loss to productivity in the United States due to CFS.”

The CDC expects to release the figure later this year, Reeves says.