TO TABLE OF CONTENTS
Chronicle Q & A: CDC
shifting to clinical studies
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
community. From 1995–98, officials diverted $12.9 million earmarked for
research to other
programs. The funds are being paid back to the
CFIDS program over the
course of several
interview, Dr. William Reeves, head of the
CFIDS program at CDC, talks
research underway at CDC — and discusses the future of the
in light of current terrorist
threats facing the nation.
What are the CDC’s main goals for CFIDS research?
We have several objectives. The first is to estimate
of the public health problem that CFS (another term for
CFIDS ) poses in the
. 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;
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
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,
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.
You have cancelled a nationwide study on the prevalence of CFIDS. Why?
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
Cost and staff resources were also
a big consideration. It didn’t
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
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
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
Much of this has been possible because of our surveillance
, Kan. Wichita is like a
poster city for mainstream
. 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
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
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
People in the
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’
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
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?
The big ones are modeling studies. In modeling studies,
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
, and another one in
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
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
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?
We are already thinking about the next clinical study.
We have done
everything we can imagine in the
clinical study — but we haven’t done any of it in great
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
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?
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.
Has the funding scandal and payback helped raise
CFIDS awareness at
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.
about the new emphasis on bioterrorism in the Bush administration? Will it erode
the budget forCFIDS?
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
For more information on the CDC’s research
CFIDS , check the CDC Web site at
Research Goes Micro
The centerpiece of the CDC’s research program for
CFIDS is a series of modeling studies looking at how the illness
develops in people who suffer “insults” to their body systems — factors such as
viruses, drug treatments, other stresses accumulated over the lifespan that may
result in CFS and similar illnesses.
These studies are all taking advantage of new technologies
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
“We’re very jazzed about these studies,”
says Dr. William Reeves,
CFIDS research program. “To
me, they’re the most exciting thing going in this field.”
The first study is based in
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
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
says she believes the microarray will someday become a routine
diagnostic tool for CFS.
Other studies also use microarray technology.
In one taking place
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
Interleukin 6 (IL-6), a protein produced by blood cells and implicated in the
CFIDS. This study will
incorporate the microarray technology — as will the follow-up clinical studies
now underway in
The IL-6 study is also funded in part by
CFIDS Association of
Out the “Big Number”
How much does CFIDS hurt the American economy? The
CDC may soon have an answer.
Based on data from a four-year surveillance study
of residents in
, 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
“This is the first time we’ve really
tried to look at the economics
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.