The following article highlights the work of Dr. Nancy Klimas, MD, an international leader in ME/CFS research, and features her succinct explanation of the basic mechanisms involved in ME/CFS. It is reproduced with kind permission from the Spring 2007 issue of University of Miami Medicine, the magazine of the Leonard M. Miller Schol of Medicine at the University of Miami (FL), where Dr. Klimas is Professor of Medicine, Psychology, Microbiology, and Immunology, and Director of the Allergy and Immunology Clinic.
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 Miller 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 Nancy Klimas, MD, 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 Miller 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 Mary 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.
“Mary 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.”
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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 Miller 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 Miller 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 Andrew 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 Michael 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.”