An investigational blood test appears to reliably distinguish individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from healthy persons and may serve as a low-cost diagnostic for the illness, new data suggest.

Rahim Esfandyarpour, PhD, from the University of California, Irvine (who was formerly at Stanford University) and colleagues reported their findings on the nanoelectronics blood-based test today in the Proceedings of the National Academy of Sciences.

There is currently no well-established biological diagnostic test for ME/CFS, an often-debilitating disease that affects about 2 million people in the United States. The diagnosis is currently based on symptoms, and a majority of individuals with the condition are believed to be undiagnosed.

The new assay detects differences in impedance patterns in response to hyperosmotic stress between blood samples from ME/CFS patients and those from healthy persons. It "can potentially establish a diagnostic biomarker and a drug-screening platform for ME/CFS in conjunction with preexisting evaluation measures.... This is a low-cost, rapid, miniaturized, minimally invasive, and highly sensitive assay," the authors write.

They say that, given the assay's significance and reliability, "we envision it has the potential to be widely employed in other research laboratories and clinics in the near future as an aid to physicians as well as to our colleagues in the ME/CFS research community."

Assay Definitively Shows ME/CFS Has Biological Roots

Ronald W. Davis, PhD, professor of biochemistry and genetics at Stanford University and director of the Stanford Genome Technology Center, California, is the senior author of the study. Davis was a coinvestigator of the landmark 2001 human genome sequencing project. He shifted the focus of his research to ME/CFS because his adult son has been bedridden and completely disabled with the illness for the past several years.

In the new study, the assay differentiated blood samples from 20 patients with moderate to severe ME/CFS (diagnosed using the 2003 Canadian Consensus Criteria) and 20 healthy control persons with 100% accuracy.

The authors note that they haven't yet tested the assay in people with other medical conditions to determine whether it is uniquely identifying individuals with ME/CFS or those with a more general state of illness.

However, for now, that's not as important as demonstrating a clear abnormality, given the skepticism among some in the medical community about the biological basis for the condition, Davis told Medscape Medical News in an interview during a recent 2-day National Institutes of Health (NIH) meeting where he had presented a preview of the data.

"It's a potential diagnostic test.... Most of the time, patients hear, 'There's nothing wrong with you.' Our major focus is to say that these patients have something wrong with them," Davis continued. "At this point, whether this tests positive in other illnesses is irrelevant. The point is, they're not healthy. Let's figure out what's wrong with them.... That's number one. The second thing would be to look at lots of other patients and see what they show."

Asked to comment on the findings during the NIH meeting, Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, Utah, said, "The biggest issue is that we don't know what [the assay] looks like in other disease processes.... But it's really [helpful] to show that it's different from normal, and hopefully it will stimulate a lot of interest trying to explain it and understand if it's present in other disease processes. The best way to know is to do the studies."

In a summary talk at the NIH meeting, Anthony Komaroff, MD, professor of medicine at Harvard Medical School, Cambridge, Massachusetts, commented, "An abnormality that perfectly distinguishes 20 patients from healthy controls obviously is a clue to some underlying biology that could be causative of the symptoms of the illness, and I'm sure that's going to be pursued."

Test Stresses the Cells With Salt

Previous studies have shown that inducing a biological stressor on peripheral blood mononuclear cells (PBMCs) via hyperosmotic stress forces the cells to consume adenosine triphosphate, a key metabolite that is hypothesized to be deficient in ME/CFS patients.

The new assay utilizes a nanoneedle bioarray that "directly measures the impedance modulations resulting from cellular and/or molecular interactions" in real time, the authors explain.

To mimic the cardinal feature of ME/CFS — the worsening of symptoms after even mild exertion, a condition known as postexertional malaise — the investigators added salt as a stressor into the patients' peripheral blood mononuclear cells incubated in their own plasma. Impedance signals dramatically rose above baseline for the ME/CFS patients but remained unchanged in the control persons. There was no overlap between the two groups.

At this point, it's not entirely clear what the signal represents. "I'm guessing it's something to do with the mitochondria, but I don't know for sure," Davis told Medscape Medical News.

Aside from being clearly different from normal, what's also clear, he noted, is that "it's been very, very reproducible — you do it again in the same patient and you get exactly the same signal. In fact, if you do the same patient a week or a month later, you get the exact same signal."

Next Steps: Larger Patient Cohort, Testing Drugs

The investigators are now expanding their work to confirm the findings in a larger cohort of patients.

They're also using the assay to screen various drugs for treating ME/CFS by adding doses to the patient samples and rerunning the diagnostic to see whether the impedance signal changes. Thus far, they've identified one candidate drug that seems to normalize it. According to a Stanford press release, "Davis and Esfandyarpour are hopeful that they can test their finding in a clinical trial in the future."

The study was funded by the Open Medicine Foundation, for which Davis is the director of the scientific advisory board. Stanford's Departments of Genetics and of Biochemistry also supported the work. Bateman has received research funding from Cortene and Lundbeck. Komaroff is a section editor on ME/CFS for UpToDate.

Proc Natl Acad Sci. Published online April 29, 2019. Abstract

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