Pilot blood test to flag chronic fatigue syndrome

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People suffering from a debilitating and often discounted disease known as chronic fatigue syndrome may soon have something they’ve been seeking for decades: scientific proof of their ailment.

Researchers at the Stanford University School of Medicine have created a blood test that can flag the disease, which currently lacks a standard, reliable diagnostic test.

“Too often, this disease is categorised as imaginary,” said Dr Ron Davis, professor of biochemistry and of genetics. When individuals with chronic fatigue syndrome seek help from a doctor, they may undergo a series of tests that check liver, kidney and heart function, as well as blood and immune cell counts, Davis said. “All these different tests would normally guide the doctor toward one illness or another, but for chronic fatigue syndrome patients, the results all come back normal,” he said.

The problem, he said, is that they’re not looking deep enough. Now, Davis; Dr Rahim Esfandyarpour, a former Stanford research associate; and their colleagues have devised a blood-based test that successfully identified participants in a study with chronic fatigue syndrome. The test, which is still in a pilot phase, is based on how a person’s immune cells respond to stress. With blood samples from 40 people – 20 with chronic fatigue syndrome and 20 without – the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals.

The diagnostic platform could even help identify possible drugs to treat chronic fatigue syndrome. By exposing the participants’ blood samples to drug candidates and rerunning the diagnostic test, the scientists could potentially see whether the drug improved the immune cells’ response. Already, the team is using the platform to screen for potential drugs they hope can help people with chronic fatigue syndrome down the line.

Davis is the senior author of the research. Esfandyarpour, who is now on the faculty of the University of California-Irvine, is the lead author.

The diagnosis of chronic fatigue syndrome, when it actually is diagnosed, is based on symptoms – exhaustion, sensitivity to light and unexplained pain, among other things – and it comes only after other disease possibilities have been eliminated. It is also known as myalgic encephalomyelitis and designated by the acronym ME/CFS. It’s estimated that 2m people in the US have chronic fatigue syndrome, but that’s a rough guess, Davis said, and it’s likely much higher.

For Davis, the quest to find scientific evidence of the malady is personal. It comes from a desire to help his son, who has suffered from ME/CFS for about a decade. In fact, it was a biological clue that Davis first spotted in his son that led him and Esfandyarpour to develop the new diagnostic tool.

The approach, of which Esfandyarpour led the development, employs a “nano-electronic assay,” which is a test that measures changes in miniscule amounts of energy as a proxy for the health of immune cells and blood plasma. The diagnostic technology contains thousands of electrodes that create an electrical current, as well as chambers to hold simplified blood samples composed of immune cells and plasma. Inside the chambers, the immune cells and plasma interfere with the current, changing its flow from one end to another. The change in electrical activity is directly correlated with the health of the sample.

The idea is to stress the samples from both healthy and ill patients using salt, and then compare how each sample affects the flow of the electrical current. Changes in the current indicate changes in the cell: the bigger the change in current, the bigger the change on a cellular level. A big change is not a good thing; it’s a sign that the cells and plasma are flailing under stress and incapable of processing it properly. All of the blood samples from ME/CFS patients created a clear spike in the test, whereas those from healthy controls returned data that was on a relatively even keel.

“We don’t know exactly why the cells and plasma are acting this way, or even what they’re doing,” Davis said. “But there is scientific evidence that this disease is not a fabrication of a patient’s mind. We clearly see a difference in the way healthy and chronic fatigue syndrome immune cells process stress.” Now, Esfandyarpour and Davis are expanding their work to confirm the findings in a larger cohort of participants.

Recruitment for the larger project, which aims to further confirm the success of the diagnostic test, is being done on a rolling basis. Those who are interested in participating should contact clinical research coordinator Anna Okumu.

In addition to diagnosing ME/CFS, the researchers are also harnessing the platform to screen for drug-based treatments, since currently the options are slim. “Using the nano-electronics assay, we can add controlled doses of many different potentially therapeutic drugs to the patient’s blood samples and run the diagnostic test again,” Esfandyarpour said.

If the blood samples taken from those with ME/CFS still respond poorly to stress and generate a spike in electrical current, then the drug likely didn’t work. If, however, a drug seems to mitigate the jump in electrical activity, that could mean it is helping the immune cells and plasma better process stress. So far, the team has already found a candidate drug that seems to restore healthy function to immune cells and plasma when tested in the assay. The drug, while successful in the assay, is not currently being used in people with ME/CFS, but Davis and Esfandyarpour are hopeful that they can test their finding in a clinical trial in the future.

All of the drugs being tested are either already approved by the US Food and Drug Administration or will soon be broadly accessible to the public, which is key to fast access and dissemination should any of these compounds pan out.

Davis is a member of Stanford Bio-X, the Stanford Cancer Institute and the Stanford Maternal & Child Health Research Institute. Other Stanford authors of the study are research scientists Neda Nemat-Gorgani and Julie Wilhelmy and research assistant, Alex Kashi.

The study was funded by the Open Medicine Foundation. Davis is the director of the foundation’s scientific advisory board.

Stanford’s departments of genetics and biochemistry also supported the work.

Abstract
There is not currently a well-established, if any, biological test to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The molecular aberrations observed in numerous studies of ME/CFS blood cells offer the opportunity to develop a diagnostic assay from blood samples. Here we developed a nanoelectronics assay designed as an ultrasensitive assay capable of directly measuring biomolecular interactions in real time, at low cost, and in a multiplex format. To pursue the goal of developing a reliable biomarker for ME/CFS and to demonstrate the utility of our platform for point-of-care diagnostics, we validated the array by testing patients with moderate to severe ME/CFS patients and healthy controls. The ME/CFS samples’ response to the hyperosmotic stressor observed as a unique characteristic of the impedance pattern and dramatically different from the response observed among the control samples. We believe the observed robust impedance modulation difference of the samples in response to hyperosmotic stress can potentially provide us with a unique indicator of ME/CFS. Moreover, using supervised machine learning algorithms, we developed a classifier for ME/CFS patients capable of identifying new patients, required for a robust diagnostic tool.

Authors
R Esfandyarpour, A Kashi, M Nemat-Gorgani, J Wilhelmy, and RW Davis

Stanford University material
Proceedings of the National Academy of Sciences abstract


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