Article Index

Model for CFS pathogenesis

Genetic Predisposition

Triggering event/ infection

Mediators (Immune, endocrine, neuroendocrine, psychosocial)

Health Outcome/ Persistence

Genetic Predisposition

Dr. Klimas went over some of HLA DR haplotypes identified in an earlier study of CFS patients that revealed these patients were at a 4 to 6-fold increased relative risk for haplotypes DR4, DR3, and DQ3 (Keller et al, 1992). Klimas explained that gene array data can separate patients into subgroups by their patterns of gene dysregulation in both immune and HPA gene clusters.

Technological progress has made it possible to analyze genes to a greater depth than we are presently able to medically understand what the data mean. Klimas further noted individuals with CFS cannot be lumped together, as they are part of subgroups and therefore should be treated differentially.

Triggering event/infection

A brief review was done of prior studies that demonstrated an association between onset of CFS and an acute viral-like illness in 60-80% of patients (Komaroff and Buchwald). Furthermore, a percentage of patients remained sick after acute viral infections, such as EBV, Q fever or Ross River Virus (according to Australian and UK research). One of the newer theories of great interest to Dr. Klimas is the possibility that only fragments of viruses (like EBV) could “trash” [i.e., dysregulate] a patient’s system.

Ronald Glaser et al.1 have found evidence that regulatory peptides encoded by EBV are expressed in CFS despite the absence of replicating virus. These peptides are known to modulate immune function by inducing pro-inflammatory and Type-2 cytokines.

A. Martin Lerner2 and his group have found evidence of a two subgroups of CFS patients with incomplete viral multiplication (CMV viral “fragments” and EBV antigen.)

[The remainder of this discussion of Lerner’s recent paper (see citation below) departs from what Dr. Klimas presented in her lecture. We reviewed Lerner’s paper and we present some of his more interesting findings in the next three paragraphs. Then we return to Dr. Klimas' lecture.]

At the same time, Lerner has found abnormal oscillating cardiac T-waves (by 24 Holter monitor) in a significant percentage of CFS patients (as opposed to controls). A smaller percentage of patients had Abnormal Cardiac Wall Motion.

Lerner suggests that the findings of incomplete viral multiplication and cardiac anomalies may be causally linked in subsets of CFS patients. The link may be direct in terms of viral damage or mediated by immune system activity. He stresses that further research must be done in this area. He also notes that “one preliminary trial of antiviral therapy (valacyclovir) in a cohort of CFS patients with single virus Epstein-Barr Virus (EBV) persistent infection is promising.”

However, Lerner also notes that the other subset of patients with CMV incomplete viral multiplication did not respond to the antiviral. He says this makes sense because the antiviral is known to have anti-EBV effects, “but does not have significant anti-HCMV activity…”

Lerner, interestingly for CFS patients, also discusses Gunther Stent’s theory regarding: “Premature scientific discovery. Premature scientific discoveries are met by the scientific community with resistance and ridicule.” [Here Lerner is saying that much of the pioneering CFS research remains in the “premature scientific discovery” category.]

Dr. Klimas indicated HHV-6 is another prevalent virus in individuals with CFS. It has been detected in 22% - 54% of patients in cross-sectional studies (Ablashi, Krueger, and Knox) and in 79% of CFS patients in longitudinal studies (HHV-6 PCR assay, Knox). Dr. Klimas emphasized that the only reliable lab for patient HHV-6 testing is the Wisconsin Viral Research Group in Milwaukee, WI. This is the laboratory in which Dr. Konstance Knox has done extensive research on the virus. However, Klimas cautioned HHV-6 does not respond to traditional antivirals, but requires aggressive treatment with very potent agents administered through IVs.

1. Glaser R et al, “Stress-associated Changes in the Steady-State Expression of Latent Epstein–Barr virus: Implications for Chronic Fatigue Syndrome and Cancer,” Brain, Behavior and Immunity 19 (2) (2005): 91-103.

2. Lerner AM et al, "Prevalence of Abnormal Cardiac Wall Motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with Chronic Fatigue Syndrome," In Vivo Jul-Aug; 18(4) (2004): 417-24.