Biomarker Research Advances in 'Chronic Fatigue Syndrome'

Miriam E. Tucker

November 08, 2016

FORT LAUDERDALE, FL — New research adds to growing evidence that the illness commonly known as chronic fatigue syndrome is biologically based, researchers report here at the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME) research and clinical conference. Some of the abnormalities identified suggest potential clinical diagnostic tests and targeted treatments.

The condition, now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) by US government bodies, has long confounded the medical community because, although patients may be severely debilitated and exhibit numerous abnormal physical findings, no specific biomarker has been found to conclusively make the diagnosis.

Instead, current diagnostic criteria, such those put forth in the February 2015 Institute of Medicine report, focus on patient-reported symptoms, including postexertional malaise, unrefreshing sleep, orthostatic hypotension, and cognitive dysfunction, along with varying levels of muscle pain or burning, influenza-like symptoms, and gastrointestinal distress, among others. It is often traced to a prolonged viral illness, but most experts believe there are multiple potential triggers.

The symptom heterogeneity, combined with the lack of specific biomarker, has resulted in skepticism among some clinicians that the condition is biologically, rather than psychologically, based.

However, studies during the last decade point to biological underpinnings. At the biennial IACFSME conference, more than 100 papers were presented that contribute further to the evidence base, according to Anthony L. Komaroff, MD, professor of medicine at Harvard University, Boston, Massachusetts, and editor-in-chief of the Harvard Health Letter.

"Case-control studies comparing patients with ME/CFS to both disease comparison groups and healthy control subjects find robust evidence of an underlying biological process involving the brain and autonomic nervous system, immune system, energy metabolism, and oxidative and nitrosative stress," Dr Komaroff said in a conference summary at the end of the meeting.

He added, "To those people out there who still question whether there is really anything wrong in this illness, my advice to them would be try consulting the evidence."

Possible Biomarkers for Diagnosis, Treatment

Jose Montoya, MD, professor of medicine at Stanford University, Palo Alto, California, presented findings from the largest such study to date, involving 192 patients with ME/CFS diagnosed by published criteria and 392 healthy but sedentary control patients. He found significant elevations in serum of patients compared with serum of control patients for 17 specific cytokines, 13 of them pro-inflammatory, that correlated with symptom severity among the patients (P values for linear trend ranged from 0.0062 to 0.0366).

The findings, Dr Montoya said, "likely substantiate many of the symptoms experienced by patients and the immune nature of the disease." And, he added, they also suggest that immune-modulating agents might be useful to treat some of the condition's inflammation-related symptoms.

Dr Komaroff commented, "Many of us for 20 to 30 years have held the hypothesis that symptoms of this illness likely are caused by increased cytokine levels in the brain due to chronic immune activation.... This is a very excellent demonstration of it. If those cytokines are the explanation for the symptoms, you would expect there to be a correlation between how high the cytokine was and how severe the symptom was, and that's what they found."

Another study, presented by Kenny L. DeMeirleir, MD, PhD, medical director of the Nevada Center for Biomedical Research in Reno, Nevada, involved 70 male and 70 female patients with ME/CFS and the same numbers of matched sedentary control participants. His team uncovered significant differences for four specific immune/inflammatory markers in venous blood samples (prostaglandin E2, interleukin 8, soluble CD14 [a surrogate marker for bacterial lipopolysaccharide], and CD57+ lymphocytes; P < .001 for each).

As a panel, the four markers correctly classified 89.5% of the males and 97.1% of the females with ME/CFS, as defined by published criteria.

Dr DeMeirleir told Medscape Medical News that he has since collected data for many more samples, and the results have held up. He also said that the panel is being used clinically to diagnose ME/CFS in his native Belgium.

Commenting on the paper in his address, Dr Komaroff called the findings "encouraging, because we need an accurate diagnostic test." However, he also cautioned that before the panel can become widely commercialized, it must first be reproduced in multiple labs, and further study must document that the results distinguish patients with ME/CFS from those with other chronic fatiguing conditions such as multiple sclerosis or lupus. And, he added, "it must be inexpensive."

Session moderator Mady Hornig, MD, associate professor of epidemiology Columbia University, New York City, told Medscape Medical News, "What I think really has to happen is for us to first use biomarkers to parse out the heterogeneity of this disorder, before we can know if it is possible to use them for diagnosis.... My feeling is that looking for a universal biomarker and trying to apply it too early, or too widely, will potentially cause us to cast out biomarkers that may be exceptionally helpful, but only in certain ME/CFS subtypes."

Added Dr Hornig, who has also done work identifying inflammatory cytokines in ME/CFS, "We clearly need more focused research on the clinical significance of biomarkers, and to understand the underlying causes of the illness."

Abnormalities Seen in Many Systems

Among several studies demonstrating brain abnormalities in ME/CFS was one involving 23 adolescents with ME/CFS and 20 matched healthy adolescents. In that study, the patients displayed significant deficits in information processing speed, sustained attention, and poorer performance on tasks of working memory compared with controls.

"So, we see many of the same cognitive problems in kids previously documented in adults. It's not surprising, but important to document, especially for the skeptical school principal," Dr Komaroff noted.

Three studies using different types of brain imaging in patients with Gulf War Illness, considered a variant of ME/CFS, showed impaired functional connectivity among different brain regions, one using positron emission tomography, another diffusion magnetic resonance imaging, and a third electroencephalograms.

Dr Komaroff noted that these are "three very different technologies, all coming to the same conclusion: that [the brain] just isn't as well-oiled a machine as it used to be, or as it is on good or better days."

Genetic differences were also found. In one study, DNA analysis in 53 patients with ME/CFS identified three single nucleotide polymorphisms that involve genes coding for a subunit of the energy molecule nicotinamide adenine dinucleotide hydrate dehydrogenase. "That's important because abundant other evidence of aberrant energy metabolism was presented at this meeting," Dr Komaroff commented.

Other studies found epigenetic phenomena, including dysfunction in genes encoding for hypo- and hypermethylation correlating with clinical symptoms, and significantly altered expression patterns for genes involved in immune regulation.

In addition, in an "unbiased" metabolomics study using mass spectrometry, metabolites that differed most between 17 patients with ME/CFS and 15 healthy participants involved pathways harvesting energy from glucose, fatty acids, and amino acids.

The finding, suggestive of a general hypometabolic state, corresponds to another recent study published in the Proceedings of the National Academy of Sciences. The specific metabolites differed between the two studies, but, Dr Komaroff said, "it's consistent. It says that some types of metabolic pathways are downregulated in this illness, whereas others like those involving immunity and inflammation are upregulated."

Moving Forward

In closing, Dr Komaroff said he was encouraged by new initiatives from the National Institutes of Health (NIH), including a newly launched intramural study in which biosamples will be analyzed from 40 confirmed postinfection patients with ME/CFS and 40 matched healthy adults, as well as an expected announcement in December of a first-ever request for applications for funded research.

In addition, meeting participants heard from an NIH official at the conference that a trans-NIH working group is collaborating with the Centers for Disease Control and Prevention's multisite ME/CFS project and other research consortia in the United States and Europe to standardize and pool clinical samples and share data. "That's the infrastructure needed to do more research in this field," Dr Komaroff said.

In the meantime, Dr Hornig told Medscape Medical News, "In addition to accelerating research on causes and treatments, we critically need to find ways to educate medical professionals about the disorder, including appropriate methods for clinical and laboratory workup and differential diagnosis, so that this patient population may be better served."

Dr DeMeirleir is medical director of the Himmunibar Foundation Center for Translational Medicine. None of the other sources in this story have financial disclosures.

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