A Vexing Enigma
New insights confront chronic fatigue syndrome
Laurel Wright was 52 years old when her well-being plummeted. That May, she began to feel inexplicably tired, day after day. “By September,” she says, “I crashed and burned.” She developed debilitating exhaustion, severe insomnia, muscle aches, and what she calls “brain fog.” Whenever she overexerted herself, aches and pains would spread throughout her body, sending her to the bed or the couch for several days at a stretch. Wright tried ducking out from her job during the day to go home and nap. Later, she cut her hours to halftime, and then went on sick leave. That was 12 years ago. She never returned to work.
Early in Wright’s illness, a doctor determined that she had developed chronic fatigue syndrome. Wright now obtains treatment for it near her home in Salt Lake City. The condition is a poorly understood disorder that affects more than 1 million people in the United States, according to a new estimate that the Centers for Disease Control and Prevention (CDC) plans to publish this fall.
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Wright received a diagnosis relatively quickly, but other patients go for years before their illness is recognized. About a decade before her own illness, Wright says, her mother “started getting the flu in the winter, and it started getting longer every year, until she had it all the time. It took her years to get diagnosed [with the syndrome].”
Like many people with the condition, Wright strictly curtails her activity. Sometimes she uses a heart-rate monitor to avoid accidentally exceeding her physical limits. She also takes pills to ease insomnia and other symptoms. But no drug has been approved to treat chronic fatigue syndrome; trial after clinical trial has produced disappointing results. Nor is there a definitive diagnostic test or an understanding of how the disorder develops.
Recent research may begin to enlighten this dark age. A major study now gives scientists an unprecedented perspective on what is awry in the bodies and brains of people who have the syndrome. And promising data on an experimental medicine indicate that the first specific drug for chronic fatigue syndrome may be nearing the market.
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An everlasting flu
Although the term chronic fatigue syndrome is still new, historical evidence suggests that the disorder has been around for centuries. Studies show that it sometimes runs in families, and it affects women more often than men.
The daylong or multiday “post-exertional malaise” that sometimes affects Wright is the “hallmark of this disease,” says internist Lucinda Bateman. For the past 6 years, Bateman’s work at her Salt Lake City medical practice, the Fatigue Consultation Clinic, has focused on Wright and other patients with chronic fatigue.
Other symptoms of chronic fatigue syndrome can include low-grade fever, sore throat, swollen lymph nodes, joint pain, memory impairment, and headache. Developing the illness is “like catching the flu and never getting better,” Bateman says.
Diagnosing chronic fatigue syndrome currently depends on first ruling out other potential causes of fatigue, such as acute viral illness or depression. Past studies of affected people have identified subtle abnormalities in the hypothalamic-pituitary-adrenal systems, which control the interactions of mood- and immunity-related hormones. But there’s no test of those hormones that indicates whether a person has chronic fatigue syndrome.
Some people develop chronic fatigue syndrome gradually, as Wright did, while in other people, it emerges full-blown on the heels of a viral infection. Epstein-Barr virus, cytomegalovirus, and herpes virus-6 are among the agents that have been linked to the disorder.
Among government-approved medicines, Bateman says, “there are no direct treatment options, only supportive treatment options.” Doctors treat chronic fatigue syndrome by helping patients to sleep better, giving medications that improve mood, and advising them on how to pace their activity so that they don’t overexert themselves.
In addition to these symptom-reducing strategies, treatments include cognitive-behavioral therapy, and what’s known as graded exercise. The latter aims to gradually increase patients’ tolerance for exertion without pushing them so hard as to trigger post-exertional malaise.
But drugs aimed at profound fatigue, the core feature of the illness, have failed in rigorous studies. A series of medical trials over the past 2 decades pitted various neurological and immune-modulating drugs against chronic fatigue syndrome.
The largest published to date, a carefully conducted test of 434 people with newly diagnosed chronic fatigue syndrome, found that the Alzheimer’s drug galantamine wasn’t significantly more effective than a placebo at reducing symptoms. The study appeared in the Sept. 8, 2004 Journal of the American Medical Association.
In earlier trials, treatments such as corticosteroids, melatonin, or phototherapy similarly showed no consistent effect.
The available therapies “work for some groups of people but not all groups of people with chronic fatigue syndrome,” says Eleanor Z. Hanna of the Office of Research on Women’s Health at the National Institutes of Health in Bethesda, Md.
The heterogeneity of patients’ responses to treatments suggests that there are different physiological “flavors” of chronic fatigue syndrome, each with a unique cause and different pattern of response to treatment approaches, says Suzanne D. Vernon, a chronic-fatigue researcher at the CDC in Atlanta. One goal of current research efforts is to figure out how to sort patients according to which flavor of the disorder they have.
Distinguishing the disease
Researchers suspect that any number of triggers may throw the immune system or another component of the physiology out of balance, thereby triggering chronic fatigue syndrome.
To investigate what distinguishes people with chronic fatigue syndrome from healthy people, Vernon and a team of investigators undertook an unusual research project. Between 1997 and 2000, they periodically interviewed some 7,000 randomly selected adults living in Wichita, Kan. Using the volunteers’ input, the researchers identified which respondents had signs of chronic fatigue. By the end of that phase of the study, 70 volunteers had had symptoms that met an accepted definition of chronic fatigue syndrome, which excludes people with other possible causes of fatigue, such as depression; 158 others had unexplained chronic fatigue that did not meet the chronic fatigue syndrome definition.
Vernon and her CDC colleague William C. Reeves invited both groups to undergo 2 days of intensive medical testing at Wesley Medical Center in Wichita, Kan. Nearly 60 people from each fatigue group agreed. The researchers also tested 55 volunteers without abnormal fatigue and 55 volunteers who had signs of fatigue along with a diagnosis of depression.
The medical workup was thorough, Vernon says. Each subject gave blood samples for genetic and hormonal tests, underwent neurological and psychological examinations, spent a night in a sleep laboratory, and submitted to other tests. In all, the researchers tallied more than 20,000 measures related to gene activity or genetic mutations and more than 500 other measures from each patient.
“We worked them up from head to toe,” says Vernon. “We didn’t want to leave any stone unturned.”
The CDC investigators “did a huge amount of testing that, in a clinical [treatment] setting, you’d never be able to justify,” Bateman adds. But that’s just the sort of work that might be necessary to yield deeper insights into the disease, she says.
To foster such insights, Vernon and Reeves turned to 20 researchers from the CDC and other U.S.–based and foreign institutions and companies. Those investigators—who included physicians, biologists, mathematicians, and other specialists—formed four teams. Each team got an identical copy of the compiled data and devised its own analytic process.
The teams collectively produced 14 reports, which appear in the April Pharmacogenomics.
One team, for example, reported that volunteers could be divided into six groups on the basis of differences in 38 or more biological variables, such as body mass index and blood concentrations of the inflammatory protein interleukin-6. Those groupings correlated well with the symptoms and diagnoses.
For example, one group included nonobese people who had sleep disturbances and chronic fatigue syndrome-related pain but had no significant depression; another group encompassed most of the healthy volunteers who had participated in the study. Uté Vollmer-Conna of the University of New South Wales in Sydney, Australia, led the team effort that produced that result. Grouping patients by subtypes could be useful for determining the causes of and developing treatments for the condition, the researchers say.
Two of the groups that focused on the genetic data from the participants found that chronic fatigue syndrome patients had patterns of abnormal activity in more than 2 dozen genes associated with immune function, cell-to-cell communication, and other physiological processes.
The similarity in the finding by those two research teams, which strengthens its validity, “just thrills me to death,” Vernon says.
Another group hunted for genetic mutations unique to chronic fatigue syndrome. Using a computer algorithm, mathematician and computer scientist Benjamin N. Goertzel of Biomind LLC in Rockville, Md., and his collaborators determined that, of the millions of variations called single-nucleotide polymorphisms, a small fraction turned up more often among people with chronic fatigue syndrome than among healthy participants. The researchers found that by analyzing just 28 of these polymorphisms, they could with 76-percent accuracy sort the volunteers into those with and those without chronic fatigue syndrome.
Vernon lauds the novel approach that the researchers used and speculates that further refinement of the method may achieve 90-percent accuracy.
While the new studies don’t put a new diagnostic test or treatment at doctors’ fingertips, they do provide evidence that chronic fatigue syndrome is a biologically distinct disease, Vernon adds. Consistent identification of the disease and its subtypes is essential for evaluating current and future drugs, Vernon says. The CDC is now undertaking a second study of similar design to replicate the findings and further investigate chronic fatigue syndrome.
Bateman and some of her patients have a more immediate cause for optimism. They recently took part in a trial of Ampligen. That immune-modulating drug, known generically as poly I: poly C12U, has been under investigation for 2 decades as a potential treatment for chronic fatigue syndrome and certain viral infections.
Past studies have not provided compelling evidence to support Ampligen’s widespread use, at least none sufficient to win the Food and Drug Administration’s approval. In 1991, for example, the regulatory agency told the drug’s manufacturer, Hemispherx Biopharma of Philadelphia, that evidence of the medicine’s safety and efficacy against chronic fatigue syndrome was “incomplete and inadequate.”
The new, company-funded study, as yet unpublished, provides strong evidence that the drug has a beneficial effect on the majority of people who have chronic fatigue syndrome, says Hemispherx chairman and chief executive officer William A. Carter. In the trial, Bateman and other investigators infused Ampligen into 93 patients twice a week for 40 weeks. Other volunteers got a fake version of the medicine.
Patients receiving the active drug who completed 40 weeks of treatment were able to exercise more aggressively than the other patients were. On a standard treadmill test, their exercise tolerance increased by 15 percent compared with that of the placebo group. That improvement might reduce or eliminate a patient’s need for help with daily activities. The investigators presented their findings in May at a medical conference in Barcelona, Spain.
The company will submit the trial results to the FDA this year, along with a request for permission to market the drug as a therapy for the syndrome, Carter says. If commercialized, Ampligen would probably cost $15,000 to $20,000 annually per patient, he says, excluding the expense of having medical staff administer it.
Despite the price tag, the medicine might reduce overall healthcare expenditures. “There is a dramatic reduction in concomitant medication use” for insomnia, pain, and other symptoms in chronic fatigue syndrome patients who receive Ampligen, Carter says.
Wright, the Salt Lake City patient, was a volunteer in the study. The treatment wasn’t easy for her.
“I started having a really bad headache when I got the drug, [as if] I had post-exertional malaise,” she recalls. “Mondays were my good days because I had my infusions on Tuesdays and Fridays. It took me about 4 months to get over the side effects.”
The suffering was worth it, she says: “I felt stronger and had more energy after about 2 weeks.”
Nevertheless, Wright is no longer taking the experimental medication. Since the trial has ended, she’d have to pay about $600 a month to get it. She laments, “I don’t have that kind of money.”