Will there ever be an objective test for CFS/ME?
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Will there ever be a test for chronic fatigue syndrome?

By Chloe Kent 01 Sep 2021

Chronic fatigue syndrome is diagnosed not through a blood test or scans, but by ruling out other conditions with similar symptoms.

Will there ever be a test for chronic fatigue syndrome?
ME as a condition doesn’t appear to have a single, unifying trigger. Credit: Shutterstock

Treating chronic fatigue syndrome, also known as myalgic encephalomyelitis (CFS/ME), starts with getting the right diagnosis – something that, for many patients, can prove elusive. Characterised by debilitating tiredness, the condition is notoriously difficult to pin down and even more challenging to treat.

CFS/ME expands far beyond exhaustion alone, with patients often also enduring flulike symptoms, musculoskeletal pain and brain fog. Around one in four people with CFS/ME are so severely unwell they are housebound.

The difficulties in obtaining a diagnosis are numerous. Patients typically undergo extensive tests for their various physical symptoms before landing on a diagnosis of CFS/ME when no other condition can be found to fit.

Symptoms can be nebulous and vary over time, leading to uncertainty about the underlying problem for both the patient and clinician and many people with CFS/ME also report being repeatedly disbelieved by doctors.

The emergence of long Covid – which some clinicians believe could be CFS/ME presenting at a large scale from one single, identifiable cause – has reopened the discussion around ME diagnosis.

Research carried out at Imperial College London recently suggested that long Covid could be diagnosed through a simple blood test. Researchers have been able to find specific autoantibodies in the blood of long Covid patients that were not found in the blood of people who recovered quickly from Covid-19 or never tested positive for the disease.

Where regular antibodies work to fight off infections, autoantibodies mistakenly target and react with a person’s own tissue and organs, rather than invading pathogens.

But while long Covid may well be a subsection of CFS/ME, the condition at large is likely to be a multisystem, multifactorial disease – not every case will have been triggered by one specific viral infection. This means that any objective diagnostic test for CFS/ME will need to be far more complex than a standalone blood test.

“ME as a condition doesn’t appear to have a single, unifying trigger,” says University of Exeter Medical School senior clinical lecturer and Action for ME medical advisor Dr David Strain. “We know that long Covid, for example, has been caused by this particular coronavirus, but there are many different viruses that can trigger the post-viral syndrome that we believe is the underlying cause of ME.”

Chronic fatigue syndrome: what are the causes?

The root causes of the disease remain unclear, although several theories exist. People with the condition often find it initially manifests as a run-of-the-mill flulike illness, leading many researchers to suspect that CFS/ME may be triggered by infectious disease. Long Covid could fall into this category.

Others believe that the condition could be caused by a change in the person’s immune system and how it reacts to infection or stress, through chronic production of cytokines, low functioning natural killer (NK) cells or differences in markers of T-cell activation.

CFS/ME may also arise from a faulty hypothalamic-pituitary-adrenal axis (HPA axis), a network that controls the body’s reaction to stress and regulates processes related to immune response, digestion, energy usage and mood.

People with CFS/ME may also have differences in the way the cells in their bodies get energy, while studies done in twins and families suggest that genes and environment might have a role to play too.

Post-exertional malaise and microRNA

There is no objective test for CFS/ME yet, but there have been steps in the right direction.

A key marker of CFS/ME is post-exertional malaise (PEM), the worsening of symptoms within 12 to 48 hours of even minor physical or mental exertion, that can then last for days or weeks. This symptom was utilised by researchers attempting to develop a molecular test for the disease in a November 2020 study published in Scientific Reports.

The researchers sought to find microRNAs tied to this symptom to try and pinpoint a specific CFS/ME biomarker. To spare patients a full bout of PEM, the research team used a therapeutic massager – an inflatable arm cuff that exerts gentle compressions – to induce a milder form. The 11 housebound CFS/ME patients involved in the initial study all reported headaches, muscle pain and fatigue following use of the massager.

The researchers drew plasma samples from the participants before and 90 minutes after this activity. The samples were then screened for differences in levels of microRNAs. The team was able to find 17 microRNAs for which the levels had shifted significantly following the test. A control group of eight age and sex-matched healthy individuals, who underwent the same activity but did not report any PEM symptoms, did not show the same changes.

This experiment was then repeated in a larger cohort of 32 CFS/ME patients and 17 matched controls. This time, the same response was found for 11 microRNAs. Seven of these 11 microRNAs were associated with regulating immune functions.

These findings will require validation in larger cohorts, to see if the test can diagnose patients at different stages and severities of ME/CFS.

Objectivity in CFS/ME

A key issue that arises during discussions of an objective test for ME is how useful the tool may be in practice. Since there appear to be multiple contributing factors that cause the condition, a test that can only pinpoint one or two may cause problems of its own.

“One of the problems that we have with doing these tests is that many CFS/ME patients have spent decades being told there’s nothing wrong with them and have had a series of normal test results,” says Strain.

“This makes getting cohorts together so that we can start looking for other underlying cases difficult, with this theory in the background that if this test is negative too it’s just another excuse for a doctor to tell them there’s nothing wrong.”

A test for the condition coming back negative because it assesses a contributing factor which only some patients experience could be devastating for those who receive get another negative result.

ME Association honorary medical advisor Dr Charles Shepherd says: “You’ve got to end up with a test which is robust and consistent before you introduce it as a gold-standard diagnostic test.

“If you’ve got a test which is fairly accurate but not totally accurate you could end up having people who have a firm blood test diagnosis of CFS/ME and then another group who probably have the condition but don’t have that gold-standard diagnosis.”

However, Strain says that the mere existence of a CFS/ME test could also be incredibly validating. Even if it worked for only a subsection of patients, it would prove that the medical system is beginning to take them seriously.

“Even if we develop a test that works for only 20% of patients, the other 80% suddenly get hope that even if there isn’t a diagnostic test that fits them yet, the fact that this one has been found means that at least there is recognition in the medical profession that there is something wrong.”