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Winter 2002

Panel: "Substantial" Evidence Links CFS, Immune System

Published research clearly suggests that immune system dysfunction plays a role in chronic fatigue syndrome (CFS), according to a panel report from a CFS symposium held late last fall.

The symposium, the third in a series on CFS, was sponsored by The Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America, the U.S. Centers for Disease Control and Prevention (CDC) and the National Institutes of Health Office of Research on Women's Health (ORWH). The series is designed to examine the role of the neurological, endocrine, circulatory and immune systems in CFS.

The panel listened to reports on CFS research from 10 doctors and scientists (see box below), then met to formulate answers to five questions:

• What is the evidence that there is dysregulation of the immune system in CFS?
• Are there examples or models of immune dysfunction that could lead to the symptoms of CFS?
• What is the evidence of the involvement of infectious agents in CFS?
• What can we learn from the existing data on interactions among the immune system, HPA axis and autonomic nervous system about the clinical presentations of CFS?
• What are the recommendations for future research? What are the recommended opportunities for research collaboration? What methodological barriers are there to the careful study of these recommendations?

The panel has completed a final statement on its findings. To preserve the ability to publish the final statement in the medical literature, the complete document is not yet available. However, after the symposium panel members agreed that:

• The immune system is involved in CFS.  There has been substantial published evidence that a large proportion of CFS patients have immunological abnormalities, including increased natural killer cell activity, increased number or activated T cells, decreased lymphocyte stimulation and increased production of some pro-inflammatory cytokines, which act as chemical messengers between cells. The panel noted that the ability to understand the exact role these changes play in the development of CFS is constrained by major limitations in the studies conducted to date.
  
• Infections may also play a role. The panel concluded that direct and indirect evidence points to the involvement of active viral or bacterial infections in the development of some cases of CFS, although no single agent has been found in all patients. For example, studies have found persistent activity of Epstein-Barr virus and/or human herpesvirus 6 in up to 30% of CFS patients.
  
• CFS is a multisystem disorder. In addition to the immune system, the endocrine and autonomic nervous systems may be implicated in CFS. There is some evidence that CFS is associated with underactivity of the hypothalamic-pituitary-adrenal axis, which could explain findings of upregulation of the immune system and an increase in circulating cytokines.
  
• More research is needed to define the immunological aspects of CFS. The panel outlined future research needs, including multiple site, longitudinal studies to: explore the possible association of infectious agents with the immunological profile seen in CFS; link immunological findings to symptoms and functional disability; and explore the use of anti-inflammatory cytokines, antivirals, antibiotics and immunomodulatory agents in the treatment of CFS. Panelists also suggested ways to overcome research barriers, such as establishing standardized methodology to differentiate between latent infections normally present in most individuals and those that are more frequently activated and associated with CFS symptoms.

Panel members say they were pleased with the symposium and its results. "It was a well-organized and well structured scientific meeting focusing on important questions," said Gerhard Krueger, MD, PhD, of the University of Texas Health Science Center at Houston. "The outcome -- as I see it -- was clear and should further assist in clarifying the pathogenesis of CFS."

• It is not uncommon for symptoms to linger for six months or more following infection with Epstein-Barr virus (EBV), Q fever or Ross-River virus, according to Andrew Lloyd, MD, of the University of New South Wales, Australia. His research group is studying people with these infections as a model for a post-infective CFS. His data demonstrate "that symptomatic manifestations are actually quite common for quite a prolonged period after these infections, which have been thought to be short-lived, lasting three to six weeks at most." Approximately 10 percent remain ill at six months, five percent at 12 months and one to two percent at 24 months. Lloyd anticipates that future work will identify predictors for both early and delayed recovery.
  
• Ron Glaser, MD, from Ohio State University discussed his hypothesis that partial reactivation of herpes viruses, like EBV, may induce immune and cytokine dysregulation and produce the CFS symptom complex in a subset of CFS patients. Data on the immunological consequences of stress in astronauts, medical students and spouses/caregivers of Alzheimer's patients indicate that stressful situations may induce partial reactivation of latent EBV. If viral reactivation is incomplete, it may hamper the ability to link a particular virus to CFS using standard PCR techniques. Dr. Glaser's group is studying several EBV enzymes in an effort to link latent EBV infection, under certain circumstances, to CFS and other illnesses.
  
• Interferon alpha is known to be a potent inducer of CFS-like symptoms. Andrew Miller, MD, and his colleagues at Emory University have found that pretreatment with an antidepressant in patients undergoing interferon alpha treatment for malignant melanoma prevented symptoms such as depression, anxiety, head and muscle aches and cognitive changes, but did not alter the development of fatigue and anorexia-type symptoms. The fatigue and anorexia symptoms preceded the mood-based symptoms and seemed to be more resistant to treatment. A similar response to antidepressants occurs in CFS, lending additional validity to Miller's work to develop a model for CFS based on interferon alpha administration.

Immunology Symposium Participants

Panel

Timothy Gerrity, PhD
(co-chair)
Georgetown University Medical Center
Washington, D.C.

Dimitris A. Papanicolaou, MD
(co-chair)
Emory University
Atlanta, Ga.

Jay D. Amsterdam, MD
University of Pennsylvania
Philadelphia, Pa.

Stephen Bingham, PhD
VA Maryland Health Care System
Perry Point, Md.

Ashley Grossman, MD
St. Bartholomew's Hospital
London, U.K.

Terry Hedrick, PhD
CFS patient, research methodologist
Cobb Island, Md.

Ronald B. Herberman, MD
University of Pittsburgh
Pittsburgh, Pa.

Gerhard Krueger, MD, PhD
University of Texas
Houston, Texas

Susan Levine, MD
Private Practice
New York, N.Y.

Nahid Mohagheghpour, PhD
Stanford Research Institute
Menlo Park, Calif.

Rebecca C. Moore
College student and person with CFS
Hyde Park, N.Y.

James Oleske, MD
University Hospital
Newark, N.J.

Christopher R. Snell, PhD
University of the Pacific
Stockton, Calif.

Facilitator

Mike Kaplan
Kaplan & Company
Charlottesville, Va.

Speakers

Joseph Cannon, PhD
Medical College of Georgia
Augusta, Ga.

Daniel J. Clauw, MD
Georgetown University Medical Center
Washington, D.C.

Sam Donta, MD
Boston VA Medical Center
Boston, Mass.

M. Ronald Glaser, PhD
Ohio State University
Columbus, Ohio

Sidney Grossberg, MD
Medical College of Wisconsin
Milwaukee, Wis.

Andrew Lloyd, MD
University of New South Wales
Sydney, Australia

Kevin Maher, PhD
University of Miami School of Medicine
Miami, Fla.

William B. Malarkey, MD
Ohio State University
Columbus, Ohio

Andrew Miller, MD
Emory University
Atlanta, Ga.
 
Robert Shapiro, MD, PhD
University of Vermont
Burlington, Vt.