Sick and Tired - Klimas, M.D.

[Guest guest]

Thanks to:

Marly C. Silverman, Founder

P.A.N.D.O.R.A. - Patient Alliance for Neuroendocrineimmune

Disorders - Organization for Research and Advocacy, Inc.

~jvr

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http://www6.miami.edu/ummedicine-magazine/featurestory2.html

University of Miami

Medicine

Volume9, Number 1, Spring 2007

The Magazine of the Leonard M. School of

Medicine

FEATURE

Sick and Tired

~~~~~~~~~~~~

By Jeanne Antol Krull

After 20 years of research, the cause of chronic Fatigue

syndrome is still elusive - but physicians and scientists at

the School of Medicine are at the forefront of efforts

to understand and develop effective treatments for the

debilitating disease.

In 1984 a woman suffering from severe fatigue, body aches, and

difficulty concentrating walked into the office of clinical

immunologist Klimas, M.D., with a medical file several

inches thick--the result of visits to more than a dozen doctors.

One piece of treatment advice she was given: " Change your hair

color and get a manicure. You'll feel better. "

But the patient knew better, telling Klimas simply, " I think there's

something wrong with my immune system. "

Those words would dramatically change the course of Klimas's

academic medical career and land her and her collaborators at

the School of Medicine at the forefront of understanding

and trying to find a treatment for a baffling and debilitating

disease that would come to be known as chronic fatigue

syndrome.

If there was something wrong with your immune system, Klimas

was the one to see in South Florida, and at the time her practice

was mainly HIV patients. Klimas sent the patient's blood sample

to colleague Ann Fletcher, Ph.D., professor of medicine,

microbiology/immunology, and psychology, and asked her to

" look at this any way you know how. " Fletcher's lab was already

doing groundbreaking work on the role of the body's natural killer

cells, which kill tumor cells or any pathogens in the blood.

" Ann reports back, 'There is something very odd about her

blood work. She has less natural killer cell function than we see

in end-stage AIDS patients, and her immune activation markers

are very high,' " Klimas recalls. " I called the patient and told her, 'I

can't tell you what's wrong, but your labs are very abnormal.' She

burst into tears, she was so happy to hear something was wrong

with her. "

It would be four more years before the Centers for Disease

Control and Prevention (CDC) would formally define chronic

fatigue syndrome, and the original definition would change over

time as scientific knowledge evolved. Before then the disease

was known as chronic Epstein-Barr virus syndrome, but that

name was eliminated as other viruses and etiologies came into

play.

The disease is characterized by profound fatigue that is not

improved by bed rest and may be worsened by physical or even

mental activity. No matter what the name or how debilitating the

symptoms, those who suffered from it--mainly women--were

called everything from hypochondriacs to just plain crackpots.

After a 17-year nursing career, Bonnie Mayer, then 45 years old,

was fulfilling a lifelong dream of getting a degree in fine arts at

Florida International University. She went to bed on April 6,

1994, feeling well and happy and woke up the next day very ill.

" The room was spinning wildly, I was extremely dizzy, sick to my

stomach, I couldn't walk, and I was very weak, " Mayer

remembers. She was diagnosed with a virus, which had affected

the inner ear or balance mechanism, but the worst was yet to

come.

" A week later I was still sick, I had extreme fatigue, I couldn't

think, I couldn't even get out of bed. " Over the next six months

she would consult six different doctors before she received a

chronic fatigue diagnosis.

" There are a lot of people who have this illness and don't know it,

and I was one of them, " Mayer says.

Patients like Mayer found some vindication late last year when

the full weight of the federal government was brought to bear

against the disease. At a news conference in Washington, the

CDC kicked off the first-ever national public awareness

campaign on the disease.

Invited to be one of only a handful of speakers was Klimas, who

spent a six-month sabbatical doing research on chronic fatigue

for the CDC. " I had been waiting for that day for a very long

time, " says Klimas. " After treating more than 2,000 chronic

fatigue syndrome patients over more than 20 years, I've seen

patients who were angry and frustrated at trying to convince their

physicians and loved ones that this is a real illness. They

experience a level of disability equal to that of patients with

late-stage AIDS and patients undergoing chemotherapy--and

now finally they have a powerful voice on their side. "

The CDC estimates that 4 million Americans have chronic

fatigue syndrome, and almost 80 percent of all cases are

undiagnosed. Among those numbers are veterans with Gulf War

illness who suffer symptoms identical to chronic fatigue.

The problem with making a diagnosis is that there is no

laboratory test, and treatment is aimed only at symptom relief

and improved function.

More than half the patients have sudden or acute onset, usually

following a viral infection. " A recent prospective study found the

one single predictor of who is going to stay sick after a viral

infection is the severity of the initial viral infection, " says Klimas.

" The other patients have a slow onset, they suffer for a year or

two before they realize they just aren't getting any better, and by

that time they have many other complicating factors such as

depression. "

When it comes to treating patients, Klimas says you don't have

to be a chronic fatigue expert--it comes down to basic clinical

principles. Patients tend to have three main problems in addition

to fatigue: sleep disruption, autonomic dysfunction (delayed

drops in blood pressure after standing), and pain.

" As you take care of each of the pieces, one by one, your patient

starts coming together and getting better and better, " says

Klimas. " In particular, the patient takes a big step forward the

day you get their sleep better. Sleep is a huge part of helping

patients feel better right from the beginning. "

Even though discovery of a cause is still elusive after more than

two decades of searching, scientists have zeroed in on several

key areas: infectious agents such as viruses, problems with

hormone regulation in the body's endocrine system,

disturbances in the autonomic regulation of blood pressure and

pulse, and immunologic dysfunction.

A multidisciplinary group led by Klimas at the School of

Medicine was among the first to recognize and report immune

system abnormalities in chronic fatigue patients. As director of

AIDS research at the Miami Veterans Affairs Medical Center,

Klimas was already working with an existing team of UM and VA

researchers on HIV, and she tapped into their expertise for this

new battle.

" We were this big, diverse, multidisciplinary team in HIV, and I

said, 'Why can't we do the same thing in chronic fatigue?'

Instead of looking at it myopically through one discipline, we're

the group that says, 'These systems are all integrated to create

what we call chronic fatigue syndrome,' " says Klimas.

In looking at what generally happens to someone with this

disease, it's easy to see how everything can go haywire. Think

about when you get a virus: You feel pretty rotten, your immune

system kicks in, everything quiets back down, and eventually you

feel better. In chronic fatigue something revs up the immune

system, but it never quiets back down.

For example, explains Klimas, " Whatever has stirred up your

immune system in the first place can end up disturbing your

sleep. When you don't sleep properly, never going into stage

three and stage four sleep, your body doesn't release the

nighttime hormones such as cortisol. A stress hormone, cortisol

is a big part of why we quiet our immune system. It peaks in the

morning when we wake up and resets the immune system for the

day. "

When that doesn't happen, the immune system that was

activated yesterday gets even more activated today and the next

day, and it starts releasing far too many cytokines, which are

molecules that can make you ache all over and disrupt stage

four sleep. These molecules can also cause adverse effects in

the brain, leading to cognitive and memory problems.

" What you end up with is this vicious cycle of fairly subtle

dysregulation between the body's hormone system, the

autonomic nervous system, and the immune system, " Klimas

says. " Everything is just a little off kilter--and instead of helping

each other, these systems together are amplifying the problem. "

Fletcher, the scientist who tested the very first patient's blood, is

the director of the E. M. Papper Clinical Immunology Laboratory

at the School and has done groundbreaking work since

the early 1980s on the immune system and, in particular, on the

role of natural killer cells in chronic fatigue.

" Initially it was quite difficult to get funding, " remembers Fletcher.

" This was seen as a hysterical condition that middle-aged

women might come down with. "

Fletcher recently received a new National Institutes of Health

(NIH) grant to study the role of specific peptides--neuropeptide

Y (NPY) and dipeptidyl-peptidase (CD26)--in the development

of chronic fatigue. These molecules are important in the

regulation of many physiological and disease processes in the

immune, nervous, and endocrine systems. The study will

examine the relationship between blood concentrations of NPY

and CD26 and the severity of chronic fatigue symptoms. And

that's not all.

Fletcher and Klimas are now recruiting 150 patients for a

five-year longitudinal NIH study that will assess patients at

baseline, again on a day when they feel good, and on a day

when they feel bad, even if they have to go to their homes to

collect the blood.

" We're going to be looking at a large menu of immunologic

markers at each of these intervals and compare them to 90

healthy subjects, " says Fletcher. " We're hoping to see which of

the markers will be instructive and will they correspond to the

symptoms. This should give us a much more complete picture of

the disease, and hopefully we can set a menu both to facilitate

the diagnosis of chronic fatigue syndrome and to measure the

efficacy of new treatments. "

Problems with the autonomic nervous system, which controls

cardiovascular, digestive, and respiratory functions (as well as

the immune system), are common in patients with chronic

fatigue. Many have difficulty with fainting spells and

lightheadedness, especially shortly after standing. Researchers

have found many of these same patients have low or

below-normal red blood cell volumes.

Klimas and Barry Hurwitz, Ph.D., professor of psychology and

medicine and part of the UM Behavioral Medicine Research

Program at the VA Medical Center, headed a four-year NIH

study that looked at whether the anemia drug Procrit could help

these patients by increasing their red blood cell volume.

" Our preliminary findings show while the drug corrected their

anemia, it did not decrease their fatigue, " says Hurwitz.

" However, we did find there was a slight improvement in their

ability to stay standing for a longer period of time without a drop

in blood pressure. Every little piece we can add to the puzzle will

help us discover the root cause or causes of this illness. "

An increase in stress plays a very significant role in managing

chronic fatigue symptoms. " On a good day I am easily

fatigued--I can get out of breath scrambling an egg, " says

Bonnie Mayer. " But if I have a particularly long, stressful day, it is

much harder to function for the next couple of days.

" For me life is an adaptation, and thanks to a great deal of family

support, my life is certainly better now than it was at the

beginning of this journey. "

For more than 20 years faculty in the Behavioral Medicine

Research Program have been studying stress management

among patients who have diseases that affect the immune

system. Much of their early work focused on HIV patients, but

there was reason to believe that stress also played a big role

among chronic fatigue patients.

A UM study conducted after Hurricane in 1992 found

that chronic fatigue patients who lived in Miami-Dade County

and went through the stress of the storm had a serious

exacerbation of their symptoms, while patients in Broward

County did not.

" We also found patients who were more optimistic and had

more social support as they moved through the hurricane did

better, " says Antoni, Ph.D., professor of psychology and

psychiatry and behavioral sciences. " We took these findings and

designed a study to evaluate the effect of a ten-week cognitive

behavioral stress management intervention group during which

chronic fatigue patients were taught techniques to deal with

stress. We found a very positive outcome on better stress and

symptom management. "

Since many chronic fatigue patients often don't feel well enough

to attend regular therapy sessions, the NIH recently funded an

extension of the study to see if the same effect can be achieved

through a telephone-based cognitive behavioral stress

management intervention. A similar program has already been

found to be beneficial among dementia caregivers.

The next frontier is clearly studying genetic factors in chronic

fatigue. Findings released earlier this year showed patients

have a genetic make-up that affects the body's ability to adapt to

change. Taking that research a step further, Klimas has received

VA funding to conduct a gene microarray analysis of chronic

fatigue and Gulf War illness patients both before and after

exercise.

" The knowledge is coming at us very quickly now. It is going to

translate into effective therapies, and I am so excited to be a

part of it, " says Klimas. " On a personal level, it is really important

to ask yourself if you made a difference that affected a lot of

people beyond your own patient base, and the answer is yes, I

think I did. But there's still a lot more to do. "