The headline reads, “Breakthrough blood test finally confirms Chronic Fatigue Syndrome.” As you might imagine, the story is far more complicated than that. Let’s start with some background of chronic fatigue syndrome, also called myalgic encephalomyelitis (ME/CFS).
As the name implies, it is a syndrome, meaning a collection of symptoms with a typical natural history – CFS is characterized by severe debilitating fatigue not relieved by rest, difficulty thinking, dizziness, chronic pain, and poor tolerance of even moderate exertion. Sometime we see this following a severe infection, especially encephalitis (brain infection). It is possible that CFS is related to long COVID.
The primary challenge in dealing with CFS is that we do not know its ultimate cause, there is no specific treatment, and there is no objective test to confirm it. The diagnosis is based on having the constellation of symptoms chronically without another diagnosis that can be the cause (so it is partly a diagnosis of exclusion). The symptoms are also what we call nonspecific, meaning that they can occur with a host of different conditions.
Patients with CFS often have depression and/or anxiety. This creates a diagnostic dilemma – are the physical symptoms caused by severe depression, or is the depression secondary to chronic debilitating symptoms? Perhaps they are comorbid – they reinforce each other without one being the ultimate cause.
Patients who suffer from CFS also have the burden of not having a definitive diagnosis. It is challenging to communicate the complexity of the syndrome and how we approach it clinically without sounding dismissive. For example, you should ask questions about anxiety and depression, but patients can interpret this as dismissing the physical symptoms as psychological. And some practitioners are skeptical that CFS is a specific illness.
Research provides some tantalizing clues, but no definitive answers. This is often because a syndrome has multiple overlapping causes, which is likely the case here. But there is some evidence for autonomic and immune dysregulation, mostly involving the brain.
The current study is an attempt to gather more information about what might be going on in CFS. It is a genome-wide association study – they are looking at lots of genomes of people with clinical CFS compared to the general population looking for any correlation. They found:
“We recruited 21,620 ME/CFS cases and performed genome-wide association studies (GWAS) for up to 15,579 cases and 259,909 population controls with European genetic ancestry. In these GWAS, we discovered eight loci that are significantly associated with ME/CFS, including three near BTN2A2, OLFM4, and RABGAP1L genes that act in the response to viral or bacterial infection.”
This is interesting research, but it is extremely premature to call this final confirmation of CFS or that there is now a test for it. First, I must point out that this is a preprint, so it has not yet been peer-reviewed. It is also a preliminary look at the data. Even if it holds up, it’s basically a fishing expedition, looking at a vast data set for any correlations. Those correlations would need to then be confirmed with a new set of data before we can say they are likely meaningful.
The study also has a major omission – they did not compare patients with CFS to patients with other diseases, only to healthy controls. It’s possible, for example, they the correlations they found are nonspecific, and could be present in many chronic illnesses, or perhaps they are just a sign of altered immunity or even a predisposition to depression.
So we are still along way from confirming that these correlations are real and then determining if they are specific to CFS, and then determine what they actually mean.
We would then want to determine if these markers mean anything clinically. For example, does a positive test predict anything about the prognosis, or response to a specific treatment, or perhaps the genetic risk of family members. Until we close the loop in this way – showing that the correlation connects to a cause or causes of the disease and tells us something useful like who should be treated and how – we can’t be sure if the correlation is real and meaningful.
Initially such a test, if the correlation holds up, may be used only to give patients a label – we would divide patients with CFS into test positive and test negative. This is useful for further research, but not for clinical management. Patients would likely find it useful to be test positive in that it would mitigate the stigma of being dismissed as not having a real illness. But this might also exacerbate this issue for patients with clinical CFS who are test negative.
What we have here is a potential new puzzle piece in the complex story of CFS. It needs to be confirmed, and if so then there needs to be lots of follow up research to know what it all means. I suspect we are still 10-20 years away from an actually useful clinical test of CFS based on these findings (if they pan out).
