There has never been a better time, technologically, for our federal health agencies to launch a significant effort to prevent and control a chronic disease that has inflicted suffering on mankind for centuries. Chronic fatigue syndrome (CFS) is the current name for an illness with many names and a long history. In 1681 Thomas Sydenham, founder of modern clinical, scientific, and public health medicine, described a disease spectrum identical to it called "muscular rheumatism." In the intervening years, assorted names have been assigned at different times and places. Today it is called Myalgic Encephalomyelitis (ME) in Europe, low natural killer cell syndrome in Japan, and postviral fatigue syndrome (PVFS) and other names elsewhere.

Names aside, rising prevalence and disability rates worldwide warrant a concerted effort by our health agencies to utilize advanced technology to rein in this illness. Furthermore, directors of these agencies should ensure that programs to uncover the cause and find effective treatments for CFS are firmly in place, appropriately staffed, and adequately funded. Applications of imaging technologies and cellular immunology have already begun to bear down on CFS, exposing parts of its underlying disease mechanism; molecular biology, microarray technology, and genomics offer opportunities for even greater progress.

There are more than 50 recorded outbreaks of this illness in the world's literature. In the latest, last February, the Japanese government reported an epidemic afflicting one-third of its working age population. This caused the Japanese prime minister to order an epidemiological study and to appoint a task force to assess the national economic impact of the illness.
CFS occurs in both epidemic and sporadic forms. Although fatigue lasting longer than six months is a defining feature, other symptoms include profound weakness impairing a person's ability to stand or sit upright and walk normal distances, memory and concentration problems comparable to mild or moderate Alzheimer's disease, and intractable muscle and joint pain. In a study of the functional ability of persons with chronic illnesses, 200 CFS sufferers scored below 2,500 normal controls and 700 persons with other chronic illnesses, including those with chronic heart failure.

Not to be confused with common fatigue--tiredness caused by overwork--chronic fatigue syndrome is a distinct illness. And, its many aliases have raised this question: Is this one disease or is it many with a similar constellation of symptoms? Hence, in 1988 the Centers for Disease Control and Prevention (CDC) published a case definition,1 updated in 1994,2 to classifiy persons with CFS.

Guided by the case definition, Leonard A. Jason at DePaul University estimates as many as 800,000 American men, women, and children suffer from CFS.3 It strikes previously healthy people, leaving them debilitated for months or years, and although most improve, fewer than 10 percent fully recover. In 1999, the Social Security Administration issued a ruling, SSR 99-2P, detailing the medical signs and laboratory findings associated with CFS.

In spite of the fact it is a major health problem in this country, CFS, unfortunately, has been an "underdeveloped" scientific area at our public health agencies for the following reasons. In 1999, CFS, at $6.7 million, was the second-lowest-funded disease in the National Institutes of Health budget, and staffing was reduced to less than one intramural full-time equivalent staff. And, between 1995 and 1998, the CDC spent 57 percent of its CFS funding on totally unrelated activities and presented false testimony to Congress about it. More unsettling, funding and staffing were decreasing while prevalence and disability rates were increasing. Consequently, the NIH and CDC have done very little to gather data about the cause of CFS or how to prevent it prompting Congress last year to order a full-fledged Government Accounting Office investigation. In the wake of this investigation, the CDC has a revamped CFS research program published on its Web site: www.cdc.gov/ncidod/diseases/cfs/research6. htm, and NIH co-chaired a CFS State-of-the-Science Conference on Oct. 23-24 in Arlington, Va., to focus on exciting areas of CFS research and identify expert investigators who might be attracted to study the illness.

Despite the noted obstacles, scientific knowledge about CFS has accrued over the past 15 years with more than 4,000 articles published in the medical literature. Summarizing the advances made by this sizable community of investigators, Anthony L. Komaroff from Harvard University states that it has been known for some time that chronic fatigue syndrome is a biological illness involving pathology of the central nervous system and immune system.4

Interestingly, as early as 1993 the World Health Organization classified CFS/ME as a neurological disease. Brain imaging scans have detected lesions and altered blood flow. Immunological studies have found increased numbers of CD8+ activated "cytotoxic" T cells (cells commonly increased when the body is fighting viral infections), low natural killer cell function, and elevated immune complexes. Based on this evidence, NIH should add CFS to the list of diseases that share the $3 billion it allocates annually for brain disorders. Specifically, experts in the field of neuroimmunology should be called upon to investigate the impact of a chronically activated immune system on central nervous system functioning.

CFS is a complex illness whose cause--be it infectious, environmental, genetic, or a combination thereof--has yet to be pinned down. CFS can follow acute mononucleosis, Lyme disease, Q fever, as well as surgery or a traumatic event. Tom Quinn of the laboratory of immunoregulation at the National Institute of Allergy and Infectious Diseases remarked recently that neurological disorders can have an infectious etiology either as a cause or a cofactor. Further, it is apparent that chronic common infections have the potential to cause long-term disability.5 Along these lines, Dharam V. Ablashi, Konstance Knox, and others have identified subgroups of CFS patients with active and reactivated HHV-6 infections, one of several suspected infectious agents.
Establishing an infectious-chronic disease link in CFS may have been hampered by inadequate technology and complacency in the past. But now, the systematic search for an infectious etiology in CFS using the most advanced molecular methods that can detect the pathogen or the host's response should be eagerly pursued by the CDC and NIH.

There is no test for CFS. A diagnosis is established by ruling out all other possible illnesses, a costly process. A promising biomarker in the 2-5A antiviral pathway comes from the work of Robert J. Suhadolnik at Temple University and Kenny DeMeirleir in Belgium who cite this as "another strong piece of evidence ... that the immune system is activated and that the object of the immune system's attack could be a chronic infection." Their test measures the levels of normal 80 kDa and 40 kDa forms of Rnase L, as well as a novel low molecular weight form (weighing 37 kDa).6 NIH only allocated $280,000 to this project in 1999; adequate funding and large-scale studies of this marker and other potential markers are urgently needed.
Addressing the severe debility associated with CFS, the late David H. Streeten, David S. Bell, and others have identified orthostatic hypotension, orthostatic tachycardia, and low blood volume in the pathogenesis of the illness. And, in addition to the cortisol deficiency discovered previously in hypothalamus-pituitary-adrenal (HPA) axis research, a recent computer tomography study found adrenal glands in CFS patients to be half the size of those in healthy controls. These endocrine, cardiac, and hematologic findings are significant additions to the growing base of CFS knowledge from many disciplines. A project to extract an integrated illness model from this database, complete with patient subgrouping, to guide directions of future research, and most importantly, the clinical management and treatment of CFS, is essential.

Finally, whether certain persons are genetically predisposed to develop CFS is being examined by Dedra Buchwald at the University of Washington with a registry of 200 sets of twins. Expanding this work by including CFS on the list of chronic illnesses studied by the National Human Genome Research Institute would be tremendously beneficial.
Thomas Sydenham rejected the speculative theories of ancient and medieval medicine and insisted on painstaking observation and careful recording, the scientific approach. Our advanced technologies enable us to observe and record in ways he could not have imagined 300 years ago. Now is the time for the leaders of our federal health agencies to deploy our powerful scientific resources to understand this complex illness and relieve the suffering it continues to inflict on mankind.

Mary E. McNamara, MBA, is a former vice president and director of research, the New Jersey CFS Association Inc.

References
1. G.P. Holmes et al., "Chronic fatigue syndrome--a working case definition," Annals of Internal Medicine, 108:387-9, 1988. (According to the Web of Science, ISI, Philadelphia, cited in more than 780 papers since publication)
2. K. Fukuda et al., "The chronic fatique syndrome--a comprehensive approach to its definition and study," Annals of Internal Medicine, 121:953-9, 1994.
3. L.A. Jason et al., "A community-based study of chronic fatigue syndrome," Archives of Internal Medicine, 159:2129-37, 1999.
4. A.L. Komaroff, "The biology of chronic fatigue syndrome," American Journal of Medicine, 108:169-71, February 2000.
5. R. Lewis, "The infection-chronic disease link strengthens." The Scientist, 14[17]:1, Sept. 4, 2000.
6. K. DeMeirleir et al., "A 37 kDa 2-5A binding protein as potential biomarker for chronic fatigue syndrome," American Journal of Medicine, 108:99-105, February 2000.

The Scientist 14[22]:35, Nov. 13, 2000
www.the-scientist.com