Despite numerous studies demonstrating biological changes related to ME/CFS, a diagnostic biomarker has not yet been identified. Biomarkers are measurable clues within the body that tell us about the presence of a disease, and can give information about disease progression.
Currently, the diagnosis of ME/CFS is largely based on self-report measures and the exclusion of other medical conditions. A lack of a biomarker leaves the door open for misunderstanding and misdiagnosis, which is particularly disheartening when we consider the debilitating nature of ME/CFS.
So much research yet no biomarker
A recent systematic review analysed 101 studies related to potential biomarkers, and demonstrated extensive evidence suggesting genetic abnormalities, immune dysfunction and neurological changes in individuals with ME/CFS compared with healthy controls. However, despite this evidence, none of the studies were able to identify a biomarker. Whilst noting biological differences is a necessary first step, this is not the only requirement in identifying a biomarker, as will be discussed later.
The systematic review identified that there were fewer than 45 patients on average per study. A small sample may not accurately represent a larger population, and the results are more susceptible to being skewed by outliers or random fluctuations. Most of the studies only required patients to fulfil the Fukuda criteria. This set of criteria has been criticised for not requiring individuals to have post-exertional malaise (PEM), which is now recognised as a cardinal feature of ME/CFS, and for being too broad and therefore risking the inclusion of patients with other illnesses.
What makes a good biomarker?
Potential biomarkers can take on different forms depending on the type of information they provide. For example, a blood or tissue sample can provide information about specific proteins or cells, whereas imaging techniques can provide a visual representation of anatomical abnormalities. Ideally, a diagnostic biomarker should have the following characteristics.
A good biomarker should be sensitive to the disease it intends to identify. This means it should correctly detect the disease in those in whom the disease is present, minimising false negatives. Therefore, if you had a room of patients with ME/CFS and individuals without ME/CFS, ideally all the patients with ME/CFS should test positive with a highly sensitive biomarker.
A good biomarker should be specific to the disease it intends to identify. This means it should be able to correctly rule out those who do not have the disease, minimising false positives. Therefore, if you had a room of patients with ME/CFS and individuals without ME/CFS, ideally all those without ME/CFS should test negative with a highly specific biomarker. There is often a trade-off between sensitivity and specificity, whereby increasing sensitivity decreases specificity and vice versa.
Reliability and reproducibility
With a reliable biomarker we would expect to consistently get similar results each time, regardless of whether multiple tests are carried out. Results should also be reproducible, meaning that if the tests are carried out by different laboratories/centres we would also expect to get similar results. Essentially a patient should not test positive for ME/CFS one day and test negative the next day; neither should their results be drastically affected by the location of testing, or the equipment used.
Non-invasive or minimally invasive
Non-invasive biomarkers are those that can be measured or detected without the need for physical interventions or invasive procedures. Examples include breath and urine biomarkers. The systematic review referred to earlier noted that the majority (79.2%) of potential biomarkers were blood-based. A blood biomarker can be considered minimally invasive compared to biomarkers measured through more invasive procedures involving surgery and tissue biopsy. Generally, less invasive methods are more cost effective and have reduced patient discomfort and risk of complications, so patients are more likely to comply with testing.
A good diagnostic biomarker should be easy to measure and provide medically useful information. Simply having a way of diagnosing ME/CFS quickly and with accuracy would be helpful both to clinicians and those who are affected by the illness. It would be even more helpful if future ME/CFS biomarkers were able to differentiate between different phenotypes (disease presentations) and allude to the severity of illness. This could help contextualise responsiveness to any treatments in development.
Despite numerous studies, there is not yet an ME/CFS biomarker which meets the above standards. Additionally, there is a desperate need for large-scale studies to validate findings.
Life with ME/CFS can be incredibly isolating because it is considered to be an ‘invisible’ condition as the debilitating nature of the disease is not immediately apparent. Unfortunately, this leads to disbelief, misunderstanding and stigma, and subsequently a reduction in support and accommodations.
Through providing clinical evidence of disease, a diagnostic biomarker would make it more likely that patients’ experiences of ME/CFS are validated and that they receive appropriate support. Furthermore, the identification of a biomarker could increase interest in ME/CFS leading to increased research funding and likelihood of development of targeted treatments.