2021: Looking back on a year of ME/CFS research

It’s the end of December, so time to review the most interesting scientific research findings on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) of the year.

We’ll only discuss each study briefly to keep this overview readable. If you’re interested in a more in-depth look at the most exciting ME/CFS research, we can highly recommend Simon McGrath’s blog and the Science for ME forum. If you feel we’ve missed some important research findings in 2021, feel free to post them in the comment section below.

B cell research from Japan

We start off with an interesting study from Japan that looked at B cells, the white blood cells that produce antibodies. Dr. Wakiro Sato and colleagues from the National Center of Neurology and Psychiatry were interested in the receptors on B cells. In several immune-mediated diseases, the repertoire of these B cell receptors is skewed. The researchers wanted to test if this was also true in ME/CFS.

Using next-generation sequencing, Sato and colleagues found clues that this might indeed be the case. Although their initial sample size was quite small, they were able to confirm their findings in a new cohort. The abnormalities were more pronounced in patients with an infectious onset of ME/CFS.

Interestingly, the Japanese findings confirmed those of a study from last year by the research team of Prof. Ian Lipkin at Columbia University despite using different methods. Lipkin’s team reported a “significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30” using mass spectrometry. Sato and colleagues found that the same IGHV region was significantly increased in ME/CFS patients in both cohorts using DNA sequencing. During an online conference, Lipkin said that the Japanese researchers had independently confirmed their findings.

Another top scientist who’s enthusiastic about the B cell findings is NIH researcher Dr. Avindra Nath. During a fascinating discussion organized by the Japanese ME/CFS Association, Nath showed his admiration of Sato’s research, stating: “Your findings are very remarkable and I think you are on the right track. B-cell abnormalities make a lot of sense.”

Butyrate in the gut

Lipkin’s team published a new study this year on fecal microbiota. They found several species of bacteria that were reduced in the gut of ME/CFS patients compared to controls and many of these were involved in the production of butyrate. The researchers followed up on this with a metabolomics analysis that confirmed that butyrate concentrations were indeed significantly lower in ME/CFS. Patients who had less of these bacteria also tended to have more fatigue symptoms.

There are quite a few things that can influence bacteria in the gut and the production of butyrate. This was, however, a well-designed study that was able to rule out some alternative explanations. First, the authors discovered that, overall, ME/CFS patients had an increased “bacterial load” meaning they had more bacteria in their stool than the controls. This is something that hadn’t been measured before in ME/CFS patients and it makes the reduced levels of butyrate-producing species even more interesting. Second, the authors were able to control for irritable bowel syndrome (IBS) comorbidity and although this influenced a lot of things, it didn’t impact the butyrate findings as these were also present in ME/CFS patients without IBS. Third, the study used a statistical method to include intake of antibiotics, probiotics, and prebiotic fiber and their findings remained robust when these were taken into account.

A 2015 ME/CFS study by the research team of Dr. Maureen Hanson also found lower levels of the genus Faecalibacterium, one of the bacteria involved in the production of butyrate that was highlighted by the Lipkin team. During an online conference this year, however, Hanson explained that this finding isn’t very specific as it is reported in other illnesses as well such as ulcerative colitis. She thought that changes in the gut were likely a downstream effect, and her team is more interested in finding the root cause of ME/CFS pathology.

No signs of neuroinflammation?

Quite a few imaging studies were published this year. Researchers used multiple methods to look at the brains of ME/CFS patients including quantitative electroencephalography (qEEG), pseudo-continuous arterial spin labeling (PCASL), diffusion tensor imaging (DTI), and a new type of high-resolution magnetic resonance spectroscopy (MRS). One of the most discussed studies of the year came from the Netherlands and used positron emission tomography (PET). The study was notorious not because of what it found but rather what it failed to find.

Let’s start with a little background first. PET is an interesting imaging technique, but it requires radioactive dye to be inserted into the body. This makes it difficult to apply to large samples of patients or healthy controls. Back in 2014, a Japanese research group published a small PET study where they reported large differences between 9 ME/CFS patients and 10 healthy controls in multiple brain regions. The results suggested increased activation of microglia, the immune defense in the central nervous system, in ME/CFS patients. The authors interpreted this as evidence of neuroinflammation. Even though the sample size was extremely small, this Japanese study has been cited multiple times over the years as evidence that neuroinflammation might be present in ME/CFS. Google Scholar counted 282 citations in total, which is a lot in the field of ME/CFS.

The Dutch study of this year tried to replicate the Japanese PET findings. The same radioactive ligand ([11C]-PK11195) was used to match the 2014 study as closely as possible. The researchers also included a third group of patients suffering from chronic fatigue following Q-fever infection. Unfortunately, the Dutch researchers failed to replicate the Japanese findings and found no evidence of neuroinflammation in either group.

The results were totally different from those of the Japanese study. While the latter found (much) higher levels of microglial activation in ME/CFS patients in all tested brain regions compared to controls, the Dutch group found lower levels in all brain regions for the ME/CFS group. It will require better and larger PET studies to figure out which result is the correct one.

Luckily the National Institutes of Health (NIH) in the US have provided funding for two research projects that are exactly planning to do this. They will use more sensitive radiotracers and will hopefully recruit a larger cohort of patients and controls. One of these studies is taking place at Stanford University while the other will be performed at the University of Alabama.

Neuroscientist Dr. Michael Van Elzakker pointed out that microglial activation has been reported in a myriad of health conditions including schizophrenia, Parkinson’s disease, and depression. So even if it is found in ME/CFS, it doesn’t mean it’s the root pathology of the illness.

The severely ill patient study

In 2021 there were also several publications on severely affected ME/CFS patients. The scientific journal Medicina devoted a special issue to this topic. It includes a testimony of Whitney Dafoe, an ME/CFS patient who became so ill that he had to receive tube feeding and could only communicate through self-made sign language.

His father Dr. Ronald Davis is a famous scientist at Stanford and has set up a study of severe ME/CFS patients. These patients are usually too sick to participate in scientific research. The severely ill patient study (SIPS) is a project supported by the Open Medicine Foundation that wanted to shine a light on this overlooked patient group. The study has been years in the making and has often been discussed in video conferences and webinars, but its main results remained unpublished until 2021. Unfortunately, due to limited funding, its scope is very limited. It includes the data of only 20 patients and 10 healthy controls.

The most interesting part of SIPS is its negative results. The authors tested antibody and antigen tests of all sorts of viral and bacterial pathogens, but these were no different in patients versus controls. They also looked at popular blood tests that are frequently performed in ME/CFS patients such as lymphocyte subsets, Natural Killer Cell function, hormones (TSH/T3/T4, FSH/LH, testosterone, estrogen…), vitamins (B12/folate, D), etc., but these also showed no significant differences. The authors note that “these lab results re-confirm the limitations of the standard laboratory test battery in ME/CFS and highlight the urgent need of developing new diagnostic tests for the disease.” There were a few differences though. Salivary cortisol levels were significantly lower in ME/CFS patients in the morning compared to controls, non-invasive sleep monitoring indicated an abnormally high number of awakenings, while cognitive tests showed slower reaction times and problems with identifying emotions.

It will be interesting to see if severely ill ME/CFS patients will be included in future scientific research. The ambitious Dutch ME/CFS research program, which has just issued its first call for proposals, included this as an explicit goal.

Genetics: no rare mutations

The most interesting data in the field of genetics came from the UK Biobank. Wang and colleagues performed a large analysis of the contribution of rare genetic mutations to various human diseases. The results were published in the prestigious journal Nature.  The supplementary material shows that data of 1232 patients with self-reported CFS is included.

The results are easily summarized: nothing really stood out. One possible explanation is that the sample size was rather small to detect rare mutations. 1232 patients may seem like a lot but in genetics studies, it’s no big deal. In comparison, the Decode ME study aims to recruit 20.000 ME/CFS patients. Another possible explanation is that rare mutations do not play a significant role in ME/CFS: genetic susceptibility to the illness may in large part be due to a combination of rather common mutations. Hopefully, the Decode ME study will provide more insight into this.

The UK Biobank study also included data on indolamine-2,3-dioxygenase (IDO) mutations which play a prominent role in the metabolic trap hypothesis. This hypothesis predicts that IDO2 mutations are more common in ME/CFS patients and is currently being pursued by Dr. Ronald Davis and colleagues at the Open Medicine Foundation. In the UK Biobank data, however, none of the IDO2-mutations were associated with ME/CFS. One big caveat though is that CFS was self-reported in this study. Patients didn’t receive a thorough medical examination to exclude alternative causes of their symptoms, as most ME/CFS diagnostic criteria require.

Impaired oxygen extraction?

Other interesting findings came from the research team of Dr. David Systrom. He and his colleagues performed more than 1500 invasive cardiopulmonary exercise tests (iCPET) in patients with unexplained exercise intolerance. With iCPET, Systrom’s team was able to measure gas exchange and blood flow through the arteries while patients were performing an exercise test. They found that a subgroup of patients had an abnormally low biventricular filling pressure or “preload failure” which could not be explained by a known heart condition. Of 223 patients with preload failure, 160 met diagnostic criteria for ME/CFS. A subgroup of these ME/CFS patients had high pulmonary blood flow but was less efficacious at extracting oxygen. According to the authors, this suggests microcirculatory dysfunction: there seems to be a problem with getting oxygen delivered to the muscle.

Other researchers are pursuing this hypothesis as well. In 2021, an interesting metabolic analysis was published by the Norwegian research team that conducted the Rituximab trial. Their findings point towards an “elevated energy strain” in ME/CFS patients as a result of “exertion-triggered tissue hypoxia”. Hypoxia means that oxygen is not available in sufficient amounts in a particular part of the body. The Norwegian study went on to characterize different metabolic phenotypes in ME/CFS patients. It is interesting to see that exercise testing and metabolic research are pointing in the same direction but thus far we only have clues rather than convincing evidence.

Handgrip strength

There were two other exercise studies that deserve a brief mention. The Dutch researchers and clinicians Drs. Van Campen & Visser have previously published data on orthostatic intolerance and reduced cerebral blood flow in ME/CFS. This year they added an analysis that demonstrates that these results cannot be explained by deconditioning. Cerebral blood flow reductions were similar in ME/CFS patients with high, moderate, or low oxygen consumption (VO2) during an exercise test.

There was also an interesting study of the German research team led by Dr. Carmen Scheibenbogen. They conducted 10 consecutive measurements of handgrip strength in more than 100 ME/CFS patients. Compared to healthy controls, ME/CFS patients showed a stronger decline over these 10 measurements. And when the same protocol was repeated an hour later, ME/CFS patients also showed larger decreases indicating a poor recovery from the first performance. There are some caveats though. The controls, for example, were not properly matched on their physical activity level. There was also a third group with cancer-related fatigue that showed similar results as the ME/CFS patients (though less pronounced).

Endothelial dysfunction

A collaboration between researchers from Austria and Chile published findings that suggest endothelial dysfunction in ME/CFS. Endothelial cells form a layer that lines the blood vessels and regulates exchanges between the blood and surrounding tissue. The authors found that several microRNAs involved in endothelial function were increased in ME/CFS patients compared to healthy controls. The interesting part of this publication is that the researchers were able to confirm their findings with an older microRNA dataset from another team that was made publicly available. That gives more confidence in the reliability of their results.

In 2021, there was also a Norwegian study that reported endothelial dysfunction in ME/CFS using different methods. The authors used “flow-mediated dilation” to test the widening of arteries in ME/CFS patients who participated in the cyclophosphamide trial. Dilation was reduced in ME/CFS patients compared to controls, but these abnormalities didn’t correlate well with ME/CFS severity.

“Complementary” findings

Then there were two studies with results of standard lab tests in a large cohort of ME/CFS patients. One was done in Spain, the other in Austria. Both bumped into an unexpected finding involving the complement system, an important part of our innate immune system.

The Spanish study unexpectedly found high levels of complement factor C1q in 107 out of 250 ME/CFS patients. The Austrian group found reduced levels of mannose-binding lectin (MBL) in approximately a third of their cohort of ME/CFS patients.

Now, there might be a connection between high levels of C1q and low levels of MBL because they have similar functions. They both cleave C4, another protein in the complement system. C1a does this in the classical pathway, while MBL is involved in the lectin pathway. If the results of the Spanish and Austrian studies are true, they might indicate that in a subgroup of ME/CFS patients there is an imbalance in which the classical pathway is overused. Hopefully, this will be investigated further in 2022.

Onset patterns in a Norwegian survey

We end our overview with some small findings that deserve a mention. At the very end of the year, there was an interesting Spanish publication. It reported that general cognition remains intact in most ME/CFS patients but that there were large deficiencies in maintained attention and fatigability during cognitive testing.

Also in 2021, researchers proposed an alternative model of cognitive behavior therapy (CBT) for ME/CFS. This version aims to help patients cope with their illness rather than treat it as a psychosomatic disorder from which patients can recover if they are willing to change their thoughts and behavior. The latter was the dominant CBT model for ME/CFS but after multiple criticisms in recent years, it is quickly losing ground.

Lastly, we would like to mention the findings of a remarkable survey. The Norwegian ME/CFS Association managed to collect responses of 5.822 ME/CFS patients. One always has to take these kinds of surveys with a grain of salt because participants may not be representative of the patient population as a whole. But in this case, the authors managed to involve a large part of the entire Norwegian ME/CFS patient population. There were lots of interesting findings, but one stood out: there was a large increase in the number of new ME/CFS cases in the period up to 2009. The authors note: “we see a peak that coincides with the swine flu epidemic”. This is not far-fetched because a decent scientific study from 2015 reported a twofold increased risk of ME/CFS following infection in the 2009 influenza A (H1N1) pandemic.

The authors of the Norwegian survey expanded their study by including responses from ME/CFS patients across Europe. They received a massive amount of 12.197 responses. It will be interesting to see if the incidence patterns around the time of the 2009 pandemic can be replicated.

That’s it for 2021. We wish you all happy holidays and many interesting ME/CFS research findings in 2022.