National Institute of Allergy and Infectious Diseases ------------------------------------------------------------------------------ National Institutes of Health U.S. Public Health Service CHRONIC FATIGUE SYNDROME ============================================================================== National Institute of Allergy an infectious Diseases ------------------------------------------------------------------------------ BBBBB AA CCCC K K GGGG RRRRR OOOO U U N N DDDD EEEEE RRRR B B A A C C K K G R R O O U U NN N D D E R R BBBBB AAAAAA C KKK G GG RRRRR O O U U N N N D D EEE RRRR B B A A C C K K G G R R O O U U N NN D D E R R BBBBB A A CCCC K K GGGG R R OOOO UUUU N N DDDD EEEEE R R -------------------------------- Backgrounder -------------------------------- CHRONIC FATIGUE SYNDROME We all get tired; most of us, at times, have felt depressed. But the enigma known as chronic fatigue syndrome (CFS) is not the ups and downs we experience in everyday life, or even the temporary persistence of such feelings in response to exceptional physical or emotional stress. The hallmark of the illness is fatigue--a fatigue that comes on suddenly and is relentless or relapsing, causing debilitating tiredness or easy fatigability in someone who has no apparent reason for feeling this way. Unlike the mind fog of a serious hangover, to which CFS has been compared, the profound weakness of CFS does not go away with a few good nights of sleep but instead slyly steals a person's vigor over months and years. Onset People diagnosed with CFS often describe its onset as sudden but not alarming because many of its symptoms--headache, sore throat, low-grade fever, fatigue and weakness, tender lymph glands, muscle and joint aches, and inability to concentrate--mimic those of the flu. But whereas flu symptoms usually go away in a few weeks, CFS symptoms persist or recur frequently for more that 6 months. ("Syndrome" means a group of symptoms that occur together but that can result from different causes.) Prevalence Contrary to the popular image, CFS is not a new "yuppie plague." This stereotype arose because those who sought help for and renewed scientific interest in CFS in the early 1980s (the illness is thought to be much older) were mainly well-educated and reasonably affluent women in their thirties and forties. Since then, physicians have seen the syndrome in people of all ages, races, and socioeconomic classes from several countries around the world. Still, young caucasian women continue to be the major group seeking medical care for CFS. Several factors may figure into this: (1) this group may more aggressively seek medical care for such symptoms; (2) like lupus and multiple sclerosis, for example, CFS may in fact turn out to affect more women than men; and (3) certain sectors of the medical community and general population are unaware or skeptical that this syndrome exists. As the medical community becomes more familiar with CFS, an increasingly diverse population with this syndrome will probably emerge. ============================================================================== 2 It is not known how many people have CFS. Until recently, no standard clinical description of the syndrome existed. CFS's symptoms overlap with those of many other diseases, making it likely that the illness has been overdiagnosed. Even now, diagnosing CFS relies heavily on first excluding similar diseases such as fibromyalgia (painful muscles), multiple sclerosis, depression, and lupus, some of which take years to become clearly manifest. However, after rigorously excluding people who have other diseases, a sizeable group of people with debilitating chronic fatigue remains, and these people may be considered to have the chronic fatigue syndrome. Historical Perspective Clinical portraits of diseases similar to CFS have appeared under different guises in the medical literature for more than a century. In the 1860s, Dr. George Beard named the syndrome neurasthenia, believing it to be a neurosis characterized by weakness and fatigue. Succeeding generations have favored but not proved different explanations--iron poor blood (anemia), low blood sugar (hypoglycemia), environmental allergy, or a bodywide yeast infections (candidiasis)--for this baffling malaise. Most recently, scientists have considered Epstein-Barr virus (EBV) as a possible cause of CFS. Some researchers believe that EBV may cause CFS in people who never recovered from mononucleosis, or in whom the virus has somehow been reactivated. Newer evidence indicates that EBV cannot, however, explain the entire spectrum of the illness. A New Definition Still, in the mid-1980s the illness became popularly tagged "chronic EBV." To create an official name and definition of the illness that reflects its broader nature, the Centers for Disease Control (CDC) recently convened a group of CFS experts. The group agreed on the name "chronic fatigue syndrome" and has now published in the medical literature strict symptoms and physical criteria that researchers can use to select patients for studies of this illness. (See the Annals of Internal Medicine, March 1988.) With these more uniform guidelines, CDC has begun studying how widespread the illness is. The National Institute of Allergy and Infectious Diseases (NIAID) is also funding a similar epidemiological study. In addition, several multifaceted studies around the country, some supported by NIAID, are now under way to characterize the viral, immunologic, physiologic, and psychologic aspects of CFS. Clinical Findings in CFS Neuropsychiatric Findings Physicians sometimes misdiagnose CFS as depression, and vice versa, because the two illnesses share many symptoms: fatigue, malaise, sleep disorders, low-grade fever, and memory and concentration problems, for example. Yet other CFS symptoms--including persistent sore throat, tender ============================================================================== 3 lymph glands, muscle and joint aches, and feelings of feverishness--do not fit the typical clinical picture of depression. Is the overlap in symptoms between CFS and depression merely a coincidence, or might it indicate that these illnesses are linked in more significant ways? NIAID-supported researchers have teamed up with neuropsychologists to explore this question; similar projects are ongoing at other research institutions. These projects encompass psychiatric evaluations, physical tests of nerve and muscle functions, explorations of brain hormone functioning, as well as visualization of the brain by sophisticated imaging techniques. Using a standard psychiatric interview, a psychiatrist at the National Institutes of Health (NIH) evaluated a small group of people with CFS to determine the incidence of a history of depression, anxiety, phobia, or other psychiatric disorder. A large percentage of these people had a past or present history of psychiatric disorder. The study was not designed to determine if CFS or the psychiatric illness came first. But based on the patients' responses, it appears that some psychiatric illnesses, particularly depression, may in part be a reaction to having CFS. Similar findings regarding psychiatric problems in patients with CFS have bee reported from other centers as well. Other NIH researchers have administered standard psychological tests to CFS patients to validate subjective reports of depression, anxiety, and problems with thinking, memory, and judgment. They found that objective test results correlate well with how severe the illness is perceived to be by the people with CFS and their doctors. A wide range of functional impairment in these areas is typically seen among people with CFS, however. These same researchers have now begun examining how people with CFS perform on tests that specifically measure nerve and muscle functions. Their objective is to pinpoint the source of CFS fatigue--that is, does it originate in the muscles or in the central nervous system? Other NIH scientists are probing the more subtle molecular interactions between the brain and the immune system. Some scientists theorize that the symptoms shared by CFS and depression could be caused by the dysregulation of one or more homones, such as the stress hormone cortisol, that act in the brain. Indirect evidence suggests that viral infections may upset a delicately balanced feedback loop regulating hormone production among the major hormone-secreting glands. Brain scans can also help locate possible areas of brain dysfunction. People with neurologic diseases such as multiple sclerosis show charcteristic brain scan abnormalities. The results of magnetic resonance imaging (MRI) studies of the brains of CFS patients, however, are inconclusive: some researchers have found no apparent abnormalities, but others have seen findings they say appear unusual. If further research verifies these abnormalities, the next step will be to determine whether viral activity is directly of indirectly causing them. All these studies represent scientists' increasing understanding that brain and immune system functions are intricately intertwined. ============================================================================== 4 Immunologic Findings Scientists at the NIAID and elsewhere have observed several immune system abnormalities in people with CFS. Many patients have relatively high antibody levels to virtually any virus measured, for example, cytomegalovirus, herpes simplex 1, or measles. (Antibodies are infection-fighting proteins.) About one-third of CFS patients studied have shown relatively high levels of immune complexes, large molecules formed when antigen (a virus or other foreign molecule) and antibody bind together. Some people with CFS also have abnormal production of interferon (an infection-fighting chemical) or abnormalities in the activity of a particular enzyme, 2'5'-oligoadenylate synthetase, induced by interferon during acute viral infections. A few years ago, a group of scientists found that some people with CFS lack antibodies to certain protein components of EBV, including one called EBNA-1 (Epstein-Barr nuclear antigen 1). They are now investigating whether the immune recognition of EBNA-1, and hence the ability to make antibodies to it, is important for controlling EBV infection. Several research groups have seen abnormal "natural killer" (NK) cell function in many patients with CFS. Unlike antibodies, which are targeted to specific antigens, NK cells nonspecifically seek and destroy abnormal cells. NK cells thus act as the first line of defense against viral infections, particularly against herpesviruses. Whether the NK dysfunction in CFS is a cause or effect of the main illness is uncertain, but researchers continue to study this problem. Overall, however, the immunologic findings in people with CFS are inconsistent and not highly reproducible. With improved immunologic tests and the more rigorous selection of patients in studies that have recently begun, scientists expect to obtain less equivocal data. Treatment Currently, no proven effective treatment for CFS exists. Through the current studies to characterize CFS, scientists hope to identify markers for the illness that will allow researchers to target treatments to specific abnomalities as well as to objectively follow the course of the illness. By measuring changes in those markers in treated patients, the effectiveness of different therapies can be evaluated. Physicians have anecdotally reported successes in small numbers of patients with a wide range of treatments including antiviral, antidepressant, and immunomodulating (boosting the immune system) drugs. Few drugs, however, have undergone rigorous clinical testing. In a double-blind, placebo- controlled study of the drug acyclovir, NIAID researchers found that as many patients reported feeling better during placebo treatment as during acyclovir treatment. This outcome diminishes claims of a therapeutic role for acyclovir in CFS. More recent carefully controlled studies revealed conflicting data regarding the value of high dose intravenous immunoglobulin: one study reported no benefit, the other reported some benefit. The lack of any proven effective treatment is frustrating to both patients and their physicians. Experts recommend that people with CFS try to maintain a healthy lifestyle by eating a balanced diet and getting adequate rest. Physical conditioning should be preserved by exercising regularly as much ============================================================================== 5 as can be tolerated short of causing more fatigue. It is important that people with CFS learn to pace themselves--physically, emotionally, and intellectually--since too much stress can exacerbate the symptoms. CFS is not a progressive disease, that is, it does not appear to worsen over time. For most people, symptoms plateau early in the course of the illness and thereafter wax and wane. A healthy person experiencing CFS- like complaints following a normal illness usually recovers in a few weeks or months; likewise, even some people with CFS have been known to spontaneously recover. Counseling may help some people cope with the uncertain prognosis and ups and downs of the illness. Finding treatments for CFS will probably be most helped by advances in basic immunology and molecular biology--understanding how the body normally responds to virus infections, what chemicals are liberated during infection, and why an infection makes us feel the way it does. Possible Causes of CFS CFS probably is not caused by any single agent. Whether several viruses can cause the same syndrome, whether the syndrome results from the synergistic effect of viruses, or whether the syndrome results from an immune or neuroimmune dysregulation is still uncertain, however. Epstein-Barr Virus Scientists have recently focused on EBV, a member of the herpesvirus family, as a possible cause of chronic fatigue. This theory arose in the early 1980s after scientists at NIAID and elsewhere independently found high levels of antibodies to EBV in patients with symptoms of chronic fatigue. (Most people have been exposed to EBV by age 30. Because EBV can cause asymptomatic infection, many people are unaware that they carry the virus. Carrying the virus chronically is probably medically unimportant.) In some of these patients, the fatigue began after they had had EBV mononucleosis. The idea that EBV could cause chronic fatigue seemed plausible because the virus establishes lifelong infection; after an acute infection, EBV retreats to salivary glands and B cells (an immune system cell), from where it can later be reactivated. More recent information casts doubt on the theory that EBV could be the sole agent causing CFS. Elevated levels, or titers, of EBV antibodies have now been found in some healthy people, too. Likewise, some people who lack EBV antibodies, and who thus have never been infected with the virus, can display CFS symptoms. Furthermore, for reasons unknown, people with other illnesses such as depression sometimes have elevated antibody titers to Epstein-Barr and other viruses. Human Herpesvirus 6 (HHV6) Another virus receiving much attention as a possible cause of CFS is a newly identified herpesvirus, human herpesvirus 6 (HHV6) (formerly known as human B lymphotropic virus, or HBLV). Like EBV, HHV6 is a latent virus: once it finds its way into the body, it resides in certain cells for life. ============================================================================== 6 Researchers at the National Cancer Institute (NCI) discovered HHV6 in 1986. Since then, they have screened several thousand blood samples from around the world to determine the prevalence of antibodies to HHV6 in people with CFS. Preliminary results of their work show that antibodies to the virus appear in most people with CFS and in a smaller but still considerable percentage of healthy people. But the researchers caution not to overinterpret their findings. First, while the sensitivity of their antibody test is good, they continue to make needed improvements. Second, latent viruses can be a barometer indicating the health of the immune system: the ability of a virus like EBV or HHV6 to reactivate, as reflected by levels of antibodies to the virus, varies inversely with the integrity of the immune system. Having high antibody titers to certain latent viruses could be just a warning sign that an immune system abnormality exists. Third, herpesviruses are prevalent worldwide and thus are easily transmitted but also well tolerated. Once the initial infection has resolved, those who carry these viruses, even people with high antibody titers, are generally healthy. Scientists expect that HHV6, like other herpesviruses, will eventually be implicated in more than one disease. Based on their preliminary evidence, however, the NCI researchers think it unlikely that HHV6 plays a straightforward role in causing CFS. Immune System Dysfunction Equally as important as the study of individual viruses is the understanding of what is unique about the immune systems of people with CFS. One theory is that these people may share an abnormal response to viruses in general. A curious finding that supports this theory is that a large number of people with CFS, 50 to 80 percent, have allergies that predate the onset of their CFS. The incidence of allergies in the U.S. population is only 17 percent. Perhaps, scientists theorize, the immune system that overreacts to allergens may also be one more likely to overrespond to other challenges, such as an infection. On the other hand, the data gathered so far indicate that the immune system in CFS is not simply overactive. Some immune functions are overactive but others appear normal or underactive. One scientist has compared the immune system to a sophisticated turbo engine. Such an engine has numerous settings on it to adjust fuel flow, air flow, and other variables. Turning one setting up will shut the engine down, but turning up a different setting will rev the engine up. Like a turbo engine, the immune system is highly complex and its proper regulation requires the increased activation of some systems and the decreased activation of other systems. Another possibility is that CFS results from a dysfunction in whatever signals the immune system to relax after an infection is over. Scientists do not know what the "return to normal" signal (or signals) is. However, some work indicates that a person's psychiatric state may influence the reset message. Studies of influenza, chronic brucellosis, and infectious mononucleosis have found that people with certain psychiatric profiles have longer periods of convalescence than others, suggesting that a person's neuropsychological state during an infection may subtly influence when the immune system stops fighting infection. ============================================================================== 7 Cyokines Another theory is that an immune system component normally active in fighting infections may be involved in CFS. Cytokines, chemicals that regulate the immune response and are released by cells during infection, have been identified as possible key players in the etiology of this illness. Some infections, the flu-like illnesses, seem more likely to trigger the production of certain cytokines. Infections such as rubella and the common cold don't involve flu-like symptoms, may not involve the same cytokines as CFS, and haven't been observed to precede CFS. Prehaps, scientists theorize, a dysfunction in the immune systems of people with CFS allows the release of cytokines during flu-like illnesses to continue unchecked. Recently, the importance of cytokines in disease processes has become a focus of increased scientific research. One cytokine, interleukin-1 (IL-1), produces fever symptoms. Studies published last year provide evidence that similar chemicals may cause the fatigue, muscle aches, and malaise also associated with flu-like illnesses. Similarly, a recent study of cancer patients receiving high doses of interleukin-2 (IL-2, another cytokine) as an experimental treatment found notable neuropsychiatric side effects, including severe lethargy, muscle aches, and memory problems. All these symptoms disappeared after treatment was stopped. Researchers have also administered interferon to monkeys and found that their brain-wave patterns looked very similar to those of people with depression. Scientists thus suspect that an overproduction of IL-1, IL-2, the interferons, and other cytokines may play a role in CFS, and they are closely examining this possibility. NIAID-Supported Basic Research Much NIAID-supported research for the past 30 years has focused on viruses, the immune system, and the interactions between the two. Basic areas of investigation include identifying the infectious agents that cause disease, determining how they stay in the body, and understanding the nature of the immune response mounted against such agents. Specifically, NIAID has supported research into herpesviruses since they were first discovered nearly 30 years ago. Of particular interest to the Institute is how these viruses establish and maintain their footholds in the body. What keeps the dormant herpesviruses in check, and, conversely, what brings them back to life? In 1985, NIAID-supported researchers reported discovering a gene whose protein product triggers latent EBV to replicate. Currently, these researchers are examining how this gene is controlled and whether differences in control of expression of this gene could be causing some symptoms of CFS. Similarly, NIAID researchers recently reported discovering a novel genetic signal that may keep herpes simplex virus 1 dormant. ============================================================================== 8 If latent viruses are implicated in causing CFS, the search for molecular switches that turn viruses on and off could help efforts to develop therapies for this illness. The studies cited illustrate how basic research can contribute to our understanding of possible molecular mechanisms underlying chronic fatigue. Conclusion Several different routes to chronic fatigue syndrome may exist. In some people, a persistent viral infection may provoke CFS symptoms, and virologists continue to explore this possibility. Vulnerability to CFS may be associated with a subtle immune system defect. It also appears likely, however, that CFS involves interactions between the immune and central nervous systems, interactions about which relatively little is now known. Scientists' concerted efforts to penetrate the complex neuroimmunologic events in CFS has created a challenging new concept of the pathology of this and other illnesses. Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892 January 1989 (revised December 1990) ============================================================================== CHRONIC FATIGUE SYNDROME SUPPORT GROUPS & RESOURCES NATIONAL ORGANIZATIONS Chronic Fatigue Immune Dysfunction Syndrome Society (formerly National CEBV Syndrome Association) Post Office Box 230108 Portland, OR 97223 (503) 684-5261 Chronic Fatigue and Immune Dysfunction Syndrome Association P.O. Box 220398 Charlotte, NC 28222 (704) 362-CFID National Chronic Fatigue Syndrome Association 3521 Broadway, Suite 222 Kansas City, MO 64111 (816) 931-4777 WASHINGTON, D.C. AREA GROUPS Woodrow Wilson Regional Library The Central Fairfax CFS/CFIDS 6101 Knollwood Drive Support Group and Forum Falls Church, VA 22041 712 Upham Place, NW (703) 590-9404 Vienna, VA 22180-4130 Contact: Pamela J. Lindsay Baltimore Hotline: (703) 242-3630 or (703) 517-9216 Contact: Esther Rodman (301) 358-1203 NOTE: The above groups are listed solely for your information because of their interest in chronic fatigue syndrome. This list does not constitute an endorsement of the organizations or any of their referrals, products, or services. FINDING A DOCTOR University-affiliated medical schools may help in locating physicians who can evaluate symptoms or who can provide an appropriate referral. U.S. PUBLIC HEALTH SERVICE The Centers for Disease Control offers a background article and provides information about CDC research, including: 1) surveillance of community health departments to determine the incidence of CFS, and 2) studies of blood samples from CFS patients to detect evidence of viral infection. Centers for Disease Control, Division of Viral Diseases Bldg. 6, Rm. 120, Atlanta, GA 30333 Phone: (404) 639-1388 NIAID Clinical Study Update: NIAID is no longer accruing new patients for its CFS studies. At present, NIAID's research involves extensive clinical and laboratory evaluations of the CFS study patients--by identifying the clinical characteristics of the disease, the researchers hope to find the cause. National Institute of Allergy and Infectious Diseases, NIH March 1991 END