Chronic Fatigue Syndrome: Wrong Name, Real Illness

Miriam E. Tucker


January 08, 2015

In This Article

Physical Findings and Biomarkers

Numerous physical abnormalities have been identified in ME/CFS patients, with stronger biological signals seen in studies measuring response to exercise[3] that differentiate patients from controls and far exceed the effects of mere deconditioning, experts say.

Such evidence includes significantly reduced oxygen consumption and workload for ME/CFS patients after treadmill tests,[4] and altered gene expression compared with controls following moderate exercise.[5]

Other biological evidence includes a recent finding of bilateral white matter atrophy in ME/CFS patients compared with controls,[6] several studies documenting significant decreases in natural killer cell cytotoxic activity, and increased levels of multiple proinflammatory cytokines.[7]

A highly significant elevation in non-Hodgkin lymphoma—which, like ME/CFS, has been linked to Epstein-Barr virus[8]—was found among ME/CFS patients aged 66-99 years in a National Cancer Institute study of data from the Surveillance, Epidemiology, and the End Results (SEER) and Medicare registries of approximately 1.2 million cancer cases and 100,000 controls, with an odds ratio of 1.29 and P value of .0000017.[9]

In a novel study of 165 consecutive patients with ME/CFS who underwent upper gastrointestinal endoscopies and antrum biopsies, 135/165 (82%) stained positive for enterovirus viral capsid protein 1 compared with just 7/34 (20%) of controls (P ≤ .001).[10]

And in another novel finding that speaks to the phenomenon's heterogeneity, approximately 2% of ME/CFS cases were found to have chromosomally integrated human herpesvirus-6 (HHV-6) as compared to just 0.2%-0.85% of the general population,[11] suggesting a specific etiology for a small proportion of cases.[12]

Responses to treatment in randomized, blinded, placebo-controlled trials also point to biological causation, including improvements with valganciclovir in a study of ME/CFS patients with elevated antibody titers to HHV-6 and Epstein-Barr virus,[13] and a preliminary trial (now being repeated in a larger patient group) in which ME/CFS patients responded to rituximab, a monoclonal antibody that destroys immune system B cells and is approved in the United States for the treatment of non-Hodgkin lymphoma and other B-cell–mediated conditions.[14]

The investigational immunomodulatory double-stranded RNA drug rintatolimod (Ampligen®; Hemispherx Biopharma, Inc.) produced objective improvement in exercise tolerance and other endpoints in a phase 3 prospective, double-blind, randomized, placebo-controlled trial of 234 subjects with long-standing, debilitating ME/CFS.[15]

The US Food and Drug Administration (FDA) rejected rintatolimod for treatment of ME/CFS in February 2013 due to insufficient efficacy and safety data, but Hemispherx continues to investigate it open-label among ME/CFS patients with low natural killer cell function, a company consultant told Medscape Medical News. (The company is also investigating the drug for treating Ebola and as an adjuvant for intranasal influenza vaccine.[16])

Dr Montoya's team at Stanford has identified several proinflammatory cytokines that are significantly elevated in samples from 200 ME/CFS patients compared with 400 age- and gender-matched controls, and that correlate with illness severity. "A dose-response effect is very powerful in biology. It's an indicator that what you are seeing is real," he told Medscape Medical News.

He believes that in ME/CFS "there is a genetic predisposition for an overwhelming inflammatory response to an infectious agent that was supposed to help the patient but is overwhelming, triggering a tremendous inflammatory cascade."

This model suggests a possible role for anti-inflammatory medications as treatment, he said, noting that both the valganciclovir and rituximab studies suggest proof of concept for that approach.

At a Stanford meeting held earlier this year, Dr Komaroff pointed out that many of the infectious agents that have been linked to ME/CFS—including Epstein-Barr virus,[17] HHV-6,[18]Coxiella burnetii (aka "Q fever"),[19] Ross River virus in Australia,[20] and various enteroviruses[21]—are ones that can't be fully eradicated by the immune system even in healthy people and/or are capable of infecting the central nervous system. This suggests the possibility that some ME/CFS patients may have a chronic, low-level encephalitis, he postulated.

Caveats and Subsets

Still, the large volume of biomarker data doesn't add up to an easy diagnostic test just yet. In the article "Chronic Fatigue Syndrome: The Current Status and Future Potentials of Emerging Biomarkers,"[22] published in June 2014, a team led by Jordan D. Dimitrakoff, PhD, MD, of Harvard School of Public Health provides an overview of published literature on selected potential biomarkers related to neurologic and immunologic components of ME/CFS, summarizing the strengths and weaknesses of each and proposing research approaches that could further their development.

Among the problems with the biomarker studies, the authors note, are small study sample sizes, the wide heterogeneity of the criteria used for patient selection leading to inconsistent findings, and the overlap of abnormalities found in ME/CFS patients with those of other conditions. Moreover, technologies used in some of the studies, such as functional MRI and cytometry, are too expensive and impractical to be employed routinely in clinical settings.

Nonetheless, they conclude, "Based on the current state of research on the topic, biomarkers offer a strong potential for characterizing [ME/CFS] subgroups in terms of clinical phenotypes, endophenotypes, prognosis, and response to therapy."


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